Pre-Implant Assessment For Optimal LV Lead Placement In CRT: ECG, ECHO, or MRI?
Matthew J. Singleton, and David D. Spragg.
Johns Hopkins Hospital and Johns Hopkins Bayview Medical Center, Baltimore, MD.
Cardiac resynchronization therapy (CRT) improves cardiac function in many patients with ventricular dyssynchrony. The optimal use of imaging for pre-implantation assessment remains a subject of debate. Here, we review the literature to date on the utility of echocardiography and cardiac MR, as well as conventional ECG, in choosing the best site for LV lead implantation. Prior to the use of imaging for pre-implantation evaluation, LV leads were placed empirically, based on average responses from population-level studies. Subsequently, patient-specific approaches have been used to maximize response. Both echocardiography and cardiac MR allow determination of areas of latest mechanical activation. Some studies have found improved response when pacing is applied at or near the site of latest mechanical activation. Similarly, both echocardiography and cardiac MR provide information about the location of any myocardial scar, which should be avoided when placing the LV lead due to variable conduction and high capture thresholds. Alternative approaches include targeting the region of latest electrical activation via measurement of the QLV interval and methods based on intraoperative hemodynamic measurements. Each of these modalities offers complementary insights into LV lead placement, so future directions include multimodality pre-implantation evaluation, studies of which are ongoing. Emerging technologies such as leadless implantable pacemakers may free implanting electrophysiologists from the constraints of the coronary sinus, making this information more useful and making non-response to CRT increasingly rare.
Corresponding Address : David Spragg, MD FHRS301 BuildingJohns Hopkins Bayview Medical Center4940 Eastern Ave.Baltimore, MD 21224
Ventricular dyssynchrony is a primary electrical disease caused by deficits in infrahisian conduction that results in mechanically inefficient cardiac pump function. Ventricular dyssynchrony, typically manifest in the form of left bundle branch block, affects roughly one-third of patients with symptomatic heart failure.1 The consequences of such include depressed ejection fraction, decreased exercise tolerance, and increased mortality.2, 3 In patients with LBBB, activation of the left ventricular lateral wall is delayed. The result is that early in systole, unopposed ventricular septal contraction generates stretch of the still quiescent lateral wall; in late systole, delayed lateral wall contraction occurs against an already pressurized blood pool, resulting in increased wall stress, poor mechanical function, and even aberrant myocardial expression of a variety of proteins including mediators of stress response, calcium handling, and myocyte coupling.4–6
Cardiac resynchronization therapy (CRT) is a pacing-based approach to treat patients with ventricular dyssynchrony. Pacing of the late-activated lateral LV to resynchronize ventricular activation has been demonstrated to improve both echocardiographic parameters (LVEF, LVESV, LA volume) and physiologic measurements (max dP/dT) of left ventricular function, as well as clinical outcomes, including NYHA class, six-minute walk time, frequency of arrhythmias, quality of life, hospitalizations for decompensated heart failure, and mortality.7–13 CRT has proven to reduce morbidity and mortality in patients with severe symptomatic CHF and LBBB, and in patients with more mild CHF symptoms.8, 14–16
However, even in trials with appropriate patient selection (LBBB, systolic dysfunction), there continues to be a substantial minority of patients who derive limited benefit from CRT--the so-called non-responders. Depending on the criteria used to determine response, whether echocardiographic, clinical, or biochemical, between 20% and 50% of patients are non-responders.17 Reasons for non-response may be multifactorial, and likely arise in part from interplay between the site of pacing and the particular substrate (i.e. scar burden, patterns of conduction) being paced.
There are two approaches to CRT lead placement--anatomic and patient-specific. Early studies investigated which anatomic sites produced the best response on a population level. Briefly, they found that basal and lateral sites produced better responses than apical and septal sites.18 Subsequently, newer studies have incorporated patient-level data, usually imaging, in seeking to find the best sites for the
patient at hand. Imaging modalities are used to avoid regions of scar
and to target either regions of latest electrical activation or regions of
latest mechanical activation. The purpose of this review is to consider
different imaging modalities – ECG, echo, and MRI – and their role
(if any) in the delivery of CRT.
Early studies in CRT efficacy as a function of pacing site
found that left lateral and posterolateral pacing resulted in greater
improvement in pump function than anterior or septal pacing.10, 18
For years, then, operators implanting LV pacing leads targeted lateral
and posterolateral CS tributaries. More recently, a number of studies
have suggested that there may be significant patient heterogeneity
in optimal pacing sites. Bordachar and colleagues found, in a small
series of patients with non-ischemic CMP, that there were frequently
patients with optimal LV function attained by pacing non-traditional
sites.19 In a complimentary series of patients with ischemic CMP,
Spragg and colleagues found similar results – namely, that there was
significant inter-patient heterogeneity in terms of LV pacing sites
that yielded optimal LV pump function.20 Finally, in a larger series
of patients receiving CRT for more mild CHF symptoms, Singh and
colleagues found that clinical response among patients with anterior,
lateral, or posterolateral sites was similar.21 Apical pacing, though,
clearly predicted worse outcomes in this large series of patients.
Based on these trials, many practitioners continue to target
lateral and posterolateral pacing sites, delivering therapy that, at the
population level, leads to good results in the majority of patients.
However, persistent issues with non-response, as well as the desire to
maximize response in an individual patient, has led to a broad area
of investigation into targeted, patient-specific LV lead placement.
Typically that tailored therapy is based on imaging of scar, of
mechanical activation timing, and (during implant procedures) of
local electrical activation timing as well.
Pre-Implantation Evaluation Modalities
The three main modalities employed in pre-implantation
evaluation to guide placement of the coronary sinus lead are ECG
(including both twelve-lead and more extensive body-surface
mapping), echocardiography, and MRI. In general, the response to
CRT is greatest when biventricular pacing serves to make the left
ventricular contraction as synchronous as possible. The two criteria
for pacing sites that might be predicted to optimize CRT response
include (1) pacing at live, non-scarred, myocardium, and (2) pacing
at the area of most delayed mechanical contraction or electrical
activation. Echocardiography and MRI elucidate both regions of latest mechanical activation and areas of scarred, non-contractile
myocardium. In contrast, ECG excels in determining the regions
of latest electrical activation; it has some abilities to localize scar, but
generally with insufficient spatial resolution to guide lead placement.
Eligibility For Crt And Non-Response
The use of advanced pre-implantation evaluation modalities to
optimize LV lead placement assumes appropriate initial patient
selection for CRT. While novel screening measures for CRT
candidacy have been explored, the simple surface ECG remains the
most commonly used and reliable tool for determining likelihood
of CRT response. In patients with severe CHF symptoms, LBBB
morphology and QRS width > 150ms have been shown to predict
greatest likelihood of CRT benefit. Narrower QRS width and/or
non-LBBB morphology, while not prohibitive, have been associated
with lower response rates. In patients with modest heart failure
symptoms, non-LBBB morphology has been shown to predict
minimal CRT response, and potentially even harm from LV
pacing. Current guidelines emphasize the results of these studies in
determining eligibility for CRT (see Figure 1, adopted from 2013
Appropriate Use Criteria).22
Patients with ischemic cardiomyopathy, by definition, have fibrosis
and scarring of ventricular myocardium. Patients with non-ischemic
cardiomyopathy, too, have been shown to have significant burdens of
ventricular scarring.23 In all patients undergoing CRT implant, then,
there is the potential for complex patterns of scar generating lines of
conduction block, unpredictable patterns of wave front propagation
from LV pacing sites, and the possibility of diminished response to
CRT. Some studies have shown that global scar burden predicts a
worse outcome than that accounted for by the decreased LVEF alone,
suggesting the electrical abnormalities in scarred myocardium pose an
additional burden.24, 25 In addition, several studies have demonstrated
that pacing near scar is associated with worse outcomes26 presumably
secondary to the unpredictable patterns of regional conduction,
variable latency, and high thresholds that are characteristic of regions
of myocardial scar.
Both echocardiography and MRI help localize regions of
scar so that leads can be placed over healthy myocardium. On
echocardiography, the ventricular wall must thicken by at least
10% with electrical activation to provide evidence of functioning
myocardium. Several studies have found that this degree of thickening
on echo is well-correlated with uptake on technetium scan, implying
that the tissue at hand is metabolically active and not scar. On MRI,
myocardial scar burden can be quantified and compared between
potential target regions using late gadolinium enhancement. The
fact that echocardiography and MRI are able to localize myocardial
scar is an important point that argues for inclusion of at least one
of these imaging modalities in preoperative planning, as neither the
surface EKG nor intraoperative capture threshold measurements are
sufficiently accurate at localizing myocardial scar and avoiding the
problems that follow pacing in adjacent regions.
Some studies have shown convincing evidence that avoiding
regions of scar is an important component of optimizing CRT
response.27, 28 While the major focus of these trials was to target
latest mechanically activated regions of myocardium, as assessed by
echocardiography, LV lead placement was also steered away from
regions of myocardial scarring. The suggestive results of those trials (described in more detail below) may be in part due to avoidance of
pacing in regions of ventricular scar.
Strategies For Pacing At The Site Of Latest Mechanical
Activation
Ventricular dyssynchrony represents the variability in time of
contraction between the different regions of the ventricle. Intuitively,
pacing at the site of latest mechanical activation is appealing as a
strategy for optimizing CRT response. There have been a number of
efforts to use either echo or MRI-based ventricular imaging protocols
to guide CRT therapy, with variable results.
Initially, studies utilizing tissue Doppler echocardiography to guide
lead placement were disappointing, including the PROSPECT trial.29
Although utilizing echocardiography to predict response to CRT
is intuitively appealing, since the correction of dyssynchrony is the
mechanism by which CRT benefits patients, investigators found that
echocardiographic measures of dyssynchrony added little predictive
power in patients who met standard indications for CRT. Several
prospective, randomized studies have since demonstrated clinical
improvement when echocardiographic measures of latest ventricular
activation as seen through speckle-tracking are used to guide CS lead
placement. The TARGET study randomized patients to either lead
placement informed by speckle-tracking echocardiographic measures
of latest ventricular activation (latest site of peak contraction with an
amplitude of greater than 10%, i.e. latest-contracting myocardium
that was not scar) versus routine, non-guided lead placement.27 The
result was clinically significant, with 70% of patients in the echoguided
arm meeting the primary endpoint of at least 15% reduction
in left ventricular end-systolic volume (LVESV), in contrast to
the 55% of patients achieving this in the control arm. Patients
who underwent echo-guided lead placement also had fewer heart
failure-related hospitalizations and decreased all-cause mortality.
The STARTER trial was similarly designed and yielded concordant
results, demonstrating decreased combined all-cause mortality and
hospitalizations for heart failure among patients in the echo-guided
arm.28 See Figure 2 for an example of speckle tracking to identify
site(s) of latest activation, as performed in the STARTER trial.28 It
should be noted that in both trials, the combined endpoint of death
and CHF hospitalization (a secondary endpoint in TARGET and the primary endpoint in STARTER) were reduced, but that the
reduction was driven entirely be lowering of CHF events rather than
mortality. These studies, while promising, were limited in terms of
sample size, number of participating centers, and need to be validated
by broader investigations.
MRI has also been used to localize the regions of latest
mechanical activation and guide LV lead placement. Compared to
echocardiography-based lead placement studies, MRI is not as welldeveloped,
but it remains promising.30 Feasibility studies have proven
that MRI-guided lead placement is possible,31, 32 but randomized
clinical trials demonstrating improved outcomes using this modality
in contrast to empiric lead placement or echocardiography-based
lead placement are still in progress.33 MRI has also been used to
quantify dyssynchrony and studies have shown that the degree of
intraventricular dyssynchrony, as measured by the time-delay between
earliest and latest regions of radial mechanical activation, has value
as a predictor of morbidity and mortality, even with CRT.34 One
interesting finding of this study is that there appears to be an upper
limit of mechanical dyssynchrony that can be corrected by CRT--
patients with the highest ventricular dyssynchrony not only fared the
worst, but also experienced no increase in LVEF with CRT. Prior
investigators have come to similar conclusions.35 The characteristics
of the dyssynchrony, including the regional circumferential strain,
can predict improvements in functional class with CRT, so MRI may
have some added value in predicting outcomes over and above any
utility in guiding lead placement.36
It should be noted, however, that although speckle-tracking
echocardiography and MRI can be used to determine the site of latest
ventricular mechanical contraction, implanting electrophysiologists
are constrained by the distribution of the CS tributaries. Consequently,
knowing the region of latest mechanical activation is necessary but
not sufficient for pacing near sites of greatest mechanical delay. In
fact, subsequent analysis of the results of the STARTER trial found
a graded clinical response that varied as a function of the distance
between the echocardiographically-demonstrated point of latest
ventricular mechanical activation and the final location of the CS
lead.37 An alternative approach that may work better within the
confines of the CS relies on finding the area of latest electrical
activation.
Strategies For Pacing At Sites Of Latest Electrical Activation
The two main modalities available for determining the site of
latest electrical activation include intraoperative measurements of
the electrical delay with the catheter positioned in the various CS
tributaries and inverse electrocardiographic imaging using bodysurface
mapping electrodes.
The most commonly employed method of finding the area of
most delayed ventricular electrical activation involves intraoperative
measurements of the QLV interval in each of the CS tributaries. The
QLV interval is defined as the time elapsed between the beginning
of the QRS complex on surface ECG and the onset of the sensed
electrogram at the LV lead as a fraction of the total QRS interval. This
approach has been validated and studies have shown that placement
of the CS lead at the site of longest QLV interval was correlated
with improved hemodynamics, including higher maximum dP/dT.38
In addition, a substudy of the SMART-AV trial showed that the
length of the QLV interval is predictive of response to CRT, in that
patients with greater electrical dyssynchrony reflected by a longer QLV interval experience more improvement with CRT.39 Similar
results were observed in the MADIT trial.21 This method has the
benefits of requiring minimal additional intraoperative time and no
ancillary studies such as speckle-tracking echo or cardiac MRI. The
fact that the QLV interval can only be measured in the tributaries
of the CS which are catheter-accessible is not a disadvantage of the
method because it is only those catheter-accessible regions that are
available for placement of the CS lead. Currently, several additional
studies are underway correlating QLV interval as measured at the CS
lead and clinical and echocardiographic response to CRT.
Figure 1. Appropriate use criteria for CRT in patients with ischemic cardiomyopathy (adopted from Reference 22). A = appropriate; M = may be appropriate; R = rarely appropriate.
Inverse electrocardiographic imaging (iECG) serves to noninvasively
estimate the electrical potentials along the epicardial
surface to determine the patterns of conduction delay, thereby
inferring optimal locations for lead placement based on areas of latest
electrical activation. Compared to the other modalities discussed
above, iECG is earlier in development and in application to patients
in clinical studies.
Figure 2. An example of speckle tracking to assess sites of latest mechanical activation (white arrow), from the STARTER trial (Reference 28).
Combined And Alternative Approaches
Since these modalities for pre-implantation assessment have
complementary strengths, a multimodality approach is currently
being trialed, comparing QLV-guided LV lead placement with imageguided
placement using speckle-tracking echo, SPECT, and cardiac
CT.40 Although the imaging will facilitate pacing at sites of latest
electromechanical activation and this is preferred to deciding based
on population-level data, even better outcomes may be achieved when
the entire endocardial surface is surveyed for optimal response via
intraventricular roving catheter. In our institutional experience, 8 of 11
patients who underwent intraoperative hemodynamic measurements
while being paced at various endocardial surfaces were found to have an
optimal pacing site that was not at traditionally used locations for LV
pacing.20 While previous investigations have partially attributed this
differential response to endocardial versus epicardial pre-excitation,41,
42 we found that the improved hemodynamic response was due to
more choices in locating the optimal site, rather than endocardial
pacing per se; pacing at endocardial sites adjacent to epicardial
sites yielded similar hemodynamic results. While promising, the
relationship between optimal intraoperative hemodynamic response
and long-term clinical outcomes needs further exploration. Notably,
determination of optimal pacing site is of limited utility as long as
operators are constrained by the distribution of the CS.
In most patients, CRT leads to improved hemodynamics,
echocardiograpic parameters, and clinical outcomes. Despite this,
a subset of patients are non-responders. Even among those who
do derive a benefit, we seek to maximize response. To these ends,
there may be a role for patient-tailored therapy via image-guided
LV lead placement. While LBBB on surface ECG remains critical
for identifying patients most likely to benefit, studies to date have
demonstrated the incremental value of echo and cardiac MRI in
targeting the latest-activated myocardium and avoiding regions of
scar. As developing technologies such as multipolar leads, endocardial
leads (among the permanently anticoagulated), and fully intracardiac
leadless pacemakers become more readily available, our therapeutic
armamentarium grows and we will be able to individualize each
patient’s treatment based on their cardiac anatomy to optimize
outcomes.43, 44 The science of patient-specific lead placement remains
in its infancy and much work remains to be done, but perhaps one day the concept of “non-responders to CRT” will be obsolescent.