DOI: 10.1111/echo.13453
O R I G I N A L I N V E S T I G AT I O N
Gauging the response to cardiac resynchronization therapy: The important interplay between predictor variables and definition of a favorable outcome Milan Petrovic MD PhD1,2 | Marija Petrovic MD1 | Goran Milasinovic MD PhD2,3 | Bosiljka Vujisic Tesic MD PhD1,2 | Danijela Trifunovic MD PhD1,2 | Olga Petrovic MD1 | Ivana Nedeljkovic MD PhD1,2 | Ivana Petrovic MD1 | Marko Banovic MD PhD1,2 | Marija Boricic-Kostic MD1 | Jelena Petrovic MD1 | Ross Arena MD PhD4 | Dejana Popovic MD PhD1,5 1 Clinic of Cardiology, Clinical Center of Serbia, Belgrade, Serbia
Aims: Selection of patients who are viable candidates for cardiac resynchronization
2
therapy (CRT), prediction of the response to CRT as well as an optimal definition of a
School of Medicine, University of Belgrade, Belgrade, Serbia 3
favorable response, all require further exploration. The purpose of this study was to
Pacemaker Center, Clinical Center of Serbia, Belgrade, Serbia
evaluate the interplay between the prediction of the response to CRT and the defini-
4 Department of Physical Therapy, College of Applied Health Sciences, University of Illinois at Chicago, Chicago, IL, USA
Methods: Seventy patients who received CRT were included. All patients met current
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Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia Correspondence Milan Petrovic, Clinic of Cardiology, Echocardiography Department, Clinical Center of Serbia, Belgrade, Serbia. Email:
[email protected] Funding information This study was partially supported by grant No. 175086 of the Ministry of Science and Technology of Republic of Serbia.
tion of a favorable outcome. guideline criteria for CRT. Forty-three echocardiographic parameters were evaluated before CRT and at 1, 3, 6, and 12 months. M-mode, 2D echocardiography, and Doppler imaging were used to quantify left ventricular (LV) systolic and diastolic function, mitral regurgitation, right ventricular systolic function, pulmonary artery pressure, and myocardial mechanical dyssynchrony. The following definitions of a favorable CRT response were used: left ventricular ejection fraction (LVEF) improvement more >5% acutely following CRT, LVEF improvement >20% at 12-month follow-up, and a LV end-systolic volume (LVESV) decrease >15% at 12-month follow-up. Results: For the LVEF improvement >5%, the best predictor was isovolumetric relaxation time (IVRT; P=.035). For improvement of LVEF >20%, the best predictors were left ventricular stroke index (LVSI; P=.044) and left ventricular fractional shortening (LVFS; P=.031). For the drop in left ventricular systolic volume (LVESV >15%), the best predictor was septal- to- lateral wall delay (ΔT) (P=.043, RR=1.023, 95% CI for RR=1.001-1.045). Conclusion: The definition of a favorable CRT response influenced the optimal predictor variable(s). Standardization of defining a favorable response to CRT is needed to guide clinical decision making processes. KEYWORDS
cardiac resynchronization therapy, definition of favorable response, predictor variable
Echocardiography 2017; 1–5
wileyonlinelibrary.com/journal/echo
© 2017, Wiley Periodicals, Inc. | 1
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PETROVIC et al.
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1 | INTRODUCTION Advanced heart failure (HF) with complete left bundle branch block, left ventricular ejection fraction (LVEF) 120 ms, and failure to favorable respond to evidence-based pharmacologic therapy continues to pose a disconcerting clinical trajectory and unfavorable prognosis.1 In this context, clinical trials have demonstrated the value of cardiac resynchronization therapy (CRT) in improving symptoms, exercise tolerance, quality of life, and long-term prognosis (ie, decreased mortality rates and duration/frequency of hospitalization) in patients with end-stage HF.2,3 However, 30% of patients with advanced HF who fulfill the aforementioned clinical phenotype do not favorably respond to CRT. As such, selection of patients who will favorably respond to CRT, optimal prediction of such a response, and defining a favorable response are all areas requiring further exploration. The aim of this study was to address these gaps in the literature. We hypothesized that the prediction of a favorable response to CRT would be influenced by the definition of such an outcome in a cohort of patients with advanced HF.
(LVSI) and cardiac index (LVCI) were assessed as LVSV and LVCO in relation to the body surface area. The changing rate of the left ventricular pressure (LVdP/dT) was assessed in an apical four-chamber view, and by the CW Doppler imaging of mitral regurgitation jet. Pulsed- wave (PW) Doppler was used to calculate the left ventricular preejection period (LVPEP), ejection time (LVET), isovolumic contraction (IVCT), and relaxation (IVRT) time. Myocardial performance index (MPI) was derived from the isovolumetric contraction and relaxation times, and LVET. PW Doppler interrogation of left ventricular outflow was performed in the apical five-chamber view proximal to the aortic annulus, and systolic outflow was traced to determine the velocity- time integral (VTILV). Mitral inflow velocities were recorded by the PW Doppler from an apical four-chamber view. Peak velocities of early (E) and late atrial (A) diastolic transmitral flow, E/A ratio, deceleration time of the E- wave (DT), isovolumetric relaxation time (IVRT), and diastolic filling time (DFT) were measured. Also, DFT in relation to the cardiac cycle length (RR) was calculated and expressed as a percentage (DFT/RR%), in order to assess the extent of the AV dyssynchrony. The severity of mitral regurgitation was graded semiquantitatively (MR+) from the color flow Doppler images using the apical four-chamber views. Mitral
2 | MATERIAL AND METHODS
regurgitation was graded on a four-point scale: none, mild1+ (jet area/ left atrial area 45%). Proximal isovelocity sur-
This prospective nonrandomized study was conducted in the
face area (PISA) and radius of PISA (PISA radius) were also assessed.
Echocardiography laboratory, Clinic of Cardiology, Clinical Center of
The left atrial (LA) diastolic dimension was assessed by the M-mode
Serbia. Between 2009 and 2012, 70 patients (53 men, 17 women),
(long parasternal axis) and with 2D echo (four-chamber view). Velocity
mean age of 59.2±9.1 years, underwent CRT. All patients met cur-
peak of a mitral regurgitation (VPMR) and mitral regurgitation velocity-
rent guideline criteria for CRT (ie, NYHA functional class III/IV, LFEV
time integral (MRVTI) were assessed by the CW Doppler (apical four
≤35%, left bundle branch block, QRS >120 ms, optimal medicament
and two-chamber views).
therapy).
Right ventricular (RV) diastolic dimension was measured with the
Echocardiographic assessment was performed in all patients be-
M-mode. Right ventricular preejection period (RVPEP), ejection time
fore the CRT (baseline data) and was subsequently followed up at 1, 3,
(RVET), pulmonary artery velocity-time integral (PAVTI), and pul-
6, and 12 months. Forty-three echocardiographic parameters were cal-
monary artery acceleration time (PAAT) were assessed by the PW
culated at each assessment. These parameters were used to quantify:
Doppler (cross-sectional parasternal view). Right ventricular systolic
(1) LV systolic and diastolic function; (2) mitral regurgitation; (3) right
pressure (RVSP) was calculated by measuring peak tricuspid regurgi-
ventricular (RV) systolic function; (4) pulmonary artery pressure param-
tation velocity with the CW Doppler. The left ventricular preejection
eters; and (5) myocardial mechanical dyssynchrony. Echocardiography
period (LVPEP) was measured from the beginning of QRS complex to
included M- mode, 2D echocardiography and Doppler imaging
the beginning of the aortic flow velocity curve recorded by the PW
(pulsed-wave [PW], continuous-wave [CW], color flow imaging, and
Doppler in apical five-chamber view. The right ventricular preejection
pulsed-wave tissue Doppler imaging [PWTDI]). All echocardiographic
period (RVPEP) was measured from the beginning of the QRS complex
recordings and analyses were performed by the same experienced in-
to the beginning of the pulmonary flow velocity curve recorded in the
vestigator using a commercially available ultrasound machine (Acuson
left cross-sectional parasternal view. The difference between LVPEP
Sequoia C 256; Siemens, Erlangen, Germany). Echocardiographic im-
and RVPEP values determined the interventricular mechanical delay
ages were obtained with a multifrequent (2-4 MHz) transducer.
(IVMD).
Left ventricular end-systolic dimension (LVESD) and end-diastolic
Interventricular dyssynchrony was evaluated by assessing the ex-
dimension (LVEDD) were assessed by M-mode (long parasternal axis).
tent of the interventricular mechanical delay (IVMD), defined as the
Left ventricular end-systolic volume (LVESV) and left ventricular end-
time difference between the left and the right ventricular preejection
diastolic volume (LVEDV) were assessed by 2D echocardiography from
periods. An IVMD >40 ms was considered indicative of interventric-
the apical four-chamber and two-chamber views (modified Simpson’s
ular dyssynchrony. Intraventricular dyssynchrony was measured by
Formula). Left ventricular stroke volume (LVSV), cardiac output (LVCO),
PWTDI, placing two sample volumes (on the basal parts of the sep-
LVEF, and fractional shortening (LVFS) were derived from previous
tum and lateral wall), and a delay ≥65 ms between peak systolic ve-
measurements of volume and dimensions. Left ventricular stroke index
locities of the septum vs lateral wall (referred to as “septal-to-lateral
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PETROVIC et al.
delay”—ΔT) was used as an indicator of the substantial intraventricular
definition for a favorable response (ie, >5% improvement in LVEF),
dyssynchrony.
more patients were categorized as in achieving this goal. As the defi-
We sought to estimate the best predictors of a favorable CRT
nition for a favorable response became more rigorous, the number
response by three primary definitions, which were used in earlier
of subjects meeting the criteria decreased. These findings are listed
studies: (1) LVEF improvement more than 5%4 acutely following CRT
in Table 1.
procedure; (2) LVEF improvement more than 20%
5-7
at 12-month fol-
The best predictors of a favorable CRT response as defined in the
low-up; and (3) LVESV drop more than 15%8,9 at 12-month follow-up.
current study are listed in Table 2. Altering the prediction of a good a favorable response to CRT altered the prediction model. For achieving a LVEF >5%, the optimal predictor was IVRT. For increasing LVEF
2.1 | Statistical analysis
>20%, the optimal predictors were LVSI and LV fractional shortening
Categorical data were summarized as frequencies and percentages.
(LVFS). For decreasing LVESV >15%, the optimal predictor was the
Continuous data were expressed as mean values±SD. Differences in
“septal-to-lateral delay”—ΔT.
baseline characteristics between responders and nonresponders were
The average values of optimal predictors of responders and nonre-
analyzed using the Student’s t test and the Wilcoxon signed-rank test.
sponders prior to CRT, for each of three different criteria of a favorable
Univariate and multivariate regression analyses were used to deter-
CRT response, are listed in the Table 3. The better response to CRT
mine predictors to a favorable CRT response according to the three
was found in patients with a shorter IVRT, higher LVSI, better LVFS,
established definitions. Predictor threshold values, as well as sensi-
and a shorter septal to lateral delay. Collectively, those with a more
tivities and specificities, were determined by receiver operating char-
favorable CRT response demonstrated higher left ventricular systolic
acteristic (ROC) curve analysis. Statistical analyses were performed
function and myocardial contractility at baseline.
using SPSS (IBM, Armonk, NY, USA) and a P5%
76%
24%
demonstrating alterations in the definition of a favorable response al-
↑LVEF >20%
60%
40%
ters the prediction model.
↓LVESV >15%
54%
46%
CRT, cardiac resynchronization therapy; LVEF, left ventricular ejection fraction; LVESV, left ventricular end-systolic volume.
prediction models used to define a favorable response requires further exploration. The results of the present study confirm this view,
QRS complex width was the first established criteria for patient selection for the CRT. However, these criteria in and of itself later proved to be an insufficient and imprecise method for CRT suitability,13
T A B L E 2 Predictors of good response to CRT
Univariate regression analysis Definition of good response to CRT
Variable a
↑LVEF >5%
IVRT
↑LVEF >20%
LVSIa LVFS
a
RR
95% CI for RR
1.021
1.002-1.041
0.95
0.903-0.999
0.863
0.755-0.987
Multivariate regression analysis ↓LVESV >15%
ΔTa
1.023
1.001-1.045
CRT, cardiac resynchronization therapy; LVEF, left ventricular ejection fraction; LVESV, left ventricular end-systolic volume; IVRT, isovolumetric relaxation time; LVSI, left ventricular stroke index; LVFS, left ventricular fractional shortening; ΔT, septal to lateral delay. a P20%
LVSI (mL/m ) LVFS (%)
↓LVESV >15%)
CRT response. LV dyssynchrony (septal to lateral wall delay in Ts>60 ms) Patients with a delay of ≥60 ms had a high likelihood of improvement in LVEF after CRT, followed by an improvement in NYHA class, quality-of- life score, and a 6-minute walking distance (Sn 76%, Sp 87.5%).17 In the
a
48±27
64±28
42.8±10.1
36.2±11.9a
group of 70 optimally medicated patients with HF that improved LVEF >20% 12 months after the CRT, Petrovic et al.18 found LVSI (Sn 75 Sp
a
14.8±4.4
12.1±4.1
67±3.6
98±45b
ΔT (ms)
was found to be the only predictor of this favorable response definition.
63.6, cutoff of 38.7 mL/m2) and LVFS (Sp 62.2, Sn 66.7, cutoff 13%) to be independent predictors of a favorable CRT response. In study group
CRT, cardiac resynchronization therapy; LVEF, left ventricular ejection fraction; LVESV, left ventricular end-systolic volume; IVRT, isovolumetric relaxation time; LVSI, left ventricular stroke index; LVFS, left ventricular fractional shortening; ΔT, septal to lateral delay. a P1
as the definition of a favorable CRT response is altered.
NYHA functional class of 6-month follow-up following CRT. During
The results in the present study are also reinforced by Fornwalt
the last 20 years, there have been numerous attempts to find an echo-
et al.21 In this previous publication, the 26 most-cited publications on
cardiographic definition of a favorable CRT response. Proposed defi-
predicting a favorable response to CRT, which collectively used 17
nitions of a favorable response have included a lack of progression of
different criteria. Agreement between different methods to define a
dyssynchrony after the CRT, as well as an increase in LVEF from more
favorable response to CRT was poor 75% of the time and strong only
4
5-7
than 5% (Fujimura) to more than 20% (Castelant; Mele).
4% of the time, which severely limits the ability to generalize results
The last
over multiple studies.21
consensus report defined a favorable response to CRT as decrease in LVESV for more than 15% as shown in the PROSPECT8 and REVERSE
In this context, the hypothesis we set out to test in the current
trials.9 In these trials, different echocardiographic methods were used,
study was supported by our findings; alteration of the definition of
such as M-mode, 2D echocardiography, speckle tracking, strain, and
a favorable CRT response alters the predictive model. As such, there
strain rates.
is currently no single optimal prediction model or universal definition
In that direction, Bleeker et al.16 evaluated the correlation be-
that can be proposed. We believe these findings are a major contribu-
tween clinical and echocardiography improvement in 144 patients.
tion of the current study. Another contribution of this paper is assess-
They found discordance between the clinical response and >15%
ment of a larger portfolio of echocardiographic measurements from
LVESV reduction in 34 pts (24%) as well as discordance in an absolute
widely available and affordable techniques, such as 2D and M-mode
LVEF improvement of >5% and the clinical response in 36 pts (25%).
echocardiography.
In the group of 25 patients with HF, Bax et al.17 found defined a
A logical evolution in this area of research is to first establish a
LVEF increase >5% after the first 24 hours following CRT, as a favorable
universally accepted definition of a favorable CRT response. This can
Definition of good response to CRT
Variable
AUC
AUC
Cutoff
Sn
Sp
↑EFLV >5%
IVRT
0.706
0.025
130.5
72.7
61.5
↑EFLV >20%
LVSI
0.698
0.012
38.7
75
63.6
↓LVESV >15%
LVFS
0.687
0.014
13
62.2
66.7
ΔT
0.690
0.022
64.5
78.6
54.5
CRT, cardiac resynchronization therapy; LVEF, left ventricular ejection fraction; LVESV, left ventricular end-systolic volume; IVRT, isovolumetric relaxation time; LVSI, left ventricular stroke index; LVFS, left ventricular fractional shortening; ΔT, septal to lateral delay.
T A B L E 4 Sensitivity, specificity, cutoffs, and area under the curve (AUC) for primary endpoint
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PETROVIC et al.
be achieved through a comprehensive prognostic assessment using various definitions in a cohort sufficiently powered with respect to number of subjects and events. Once an optimal definition is put forth, work can begin in establishing universally accepted prediction models. Given the importance of CRT in the management of patients with HF, continued research in this area is warranted.
4.1 | Limitations of study The major limitations of this study are the nonrandomized design, relatively small number of patients, and single-center study. Also, we used only echo parameters to evaluate endpoints, with no clinical correlations in our study population. However, there are no previous studies evaluating predictors of a favorable CRT response, using different definitions in a single cohort. The current study attempted to address this gap in the literature, assessing the interplay between favorable CRT response definition and prediction, and represent new contribution for prediction to CRT, and therefore needs to be further tested in a large number of patients.
5 | CONCLUSION The results of the present study indicate prediction of a favorable CRT response depends strongly on how this is defined. Therefore, there is currently no widely accepted prediction model. Precise definition of a favorable response to CRT should be established by future research.
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How to cite this article: Petrovic M, Petrovic M, Milasinovic G, et al. Gauging the response to cardiac resynchronization therapy: The important interplay between predictor variables and definition of a favorable outcome. Echocardiography. 2017;00:1-5. doi:10.1111/echo.13453.
