Native Electrocardiographic QRS Duration after Cardiac Resynchronization Therapy: The Impact on Clinical Outcomes and Prognosis

Accepted Manuscript Title: Native Electrocardiographic QRS Duration after Cardiac Resynchronization Therapy: the Impact on Clinical Outcomes and Prognosis Author: Oguz Karaca, Beytullah Cakal, Mehmet Onur Omaygenc, Haci Murat Gunes, Sinem Deniz Cakal, Filiz Kizilirmak, Tayyar Gokdeniz, Irfan Barutcu, Bilal Boztosun, Fethi Kilicaslan PII: DOI: Reference:

S1071-9164(16)30015-X http://dx.doi.org/doi: 10.1016/j.cardfail.2016.04.001 YJCAF 3745

To appear in:

Journal of Cardiac Failure

Received date: Revised date: Accepted date:

9-9-2015 9-3-2016 1-4-2016

Please cite this article as: Oguz Karaca, Beytullah Cakal, Mehmet Onur Omaygenc, Haci Murat Gunes, Sinem Deniz Cakal, Filiz Kizilirmak, Tayyar Gokdeniz, Irfan Barutcu, Bilal Boztosun, Fethi Kilicaslan, Native Electrocardiographic QRS Duration after Cardiac Resynchronization Therapy: the Impact on Clinical Outcomes and Prognosis, Journal of Cardiac Failure (2016), http://dx.doi.org/doi: 10.1016/j.cardfail.2016.04.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Native Electrocardiographic QRS Duration after Cardiac

2

Resynchronization Therapy: The Impact on Clinical

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Outcomes and Prognosis

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Oguz Karaca Asst. Prof.a, Beytullah Cakal Asst. Prof.a, Mehmet Onur Omaygenc Asst.

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Prof.a, Haci Murat Gunes Asst. Prof.a, Sinem Deniz Cakal MD.a, Filiz Kizilirmak Asst.

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Prof.a, Tayyar Gokdeniz Assoc. Prof.a, Irfan Barutcu Prof.a, Bilal Boztosun Prof.a, Fethi

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Kilicaslan Prof.b

9 a

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b

Medipol University Faculty of Medicine, Department of Cardiology, Istanbul, TURKEY

Medipol University Faculty of Medicine, Department of Cardiac Electrophysiology, Istanbul, TURKEY

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Short Title: Native QRS narrowing predicts outcomes after CRT

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Corresponding Author: Oguz Karaca, MD

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Address: Medipol University Faculty of Medicine, Cardiology Department

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TEM Otoyolu Goztepe Cikisi No 1, 34214 Bagcilar, Istanbul, TURKEY

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Fax: +90 212 460 70 70, Mobile: +90 505 355 76 00, E-mail: [email protected]

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Highlights 

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Reversal of electrical remodeling (RER) after CRT is determined by narrowing of the intrinsic electrocardiographic QRS duration.



5

The present study addressed the impact of RER on echocardiographic and prognostic outcomes after CRT.

6



RER leads to higher rates of functional and volumetric CRT response.

7



Native QRS narrowing relates to improvement in both MR severity and mitral geometry.

8



Patients with RER derive more benefit from CRT in terms of death and hospitalization.

9

ABSTRACT

10

Background: We investigated whether reversed electrical remodeling (RER) defined as

11

narrowing of the native electrocardiographic QRS duration after cardiac resynchronization

12

therapy (CRT) might predict prognosis and improvement in echocardiographic outcomes.

13

Methods and Results: A total of 110 CRT recipients was retrospectively analyzed for the end-

14

points of death and hospitalization during 18 ± 3 months. Native QRS durations were recorded at

15

baseline and 6-months after CRT (when pacing was switched-off to obtain an ECG) to determine

16

RER. CRT response and mitral regurgitation (MR) improvement were defined as the ≥ 15%

17

reduction in LVESV and as the absolute reduction in regurgitant volume (RegV) at 6 months,

18

respectively. Overall, 48 patients (44%) had RER which was associated with functional

19

improvement (77% vs. 34%, p < 0.001) and CRT response (81% vs. 52%, p < 0.001) compared

20

to those without RER. The change in the intrinsic QRS duration correlated with the reduction in

21

RegV (r= 0.51, p < 0.001) and in tenting area (r= 0.34, p< 0.001). RER was a predictor of MR

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improvement (p= 0.023), survival (p= 0.043) and event-free survival (p= 0.028) by multivariate

2

analyses.

3

Conclusions: Narrowing of the intrinsic QRS duration is associated with functional and

4

echocardiographic CRT response, reduction in MR, and favorable prognosis after CRT.

5 6

Key words: Native QRS duration, reversed electrical remodeling, cardiac resynchronization

7

therapy response, mitral regurgitation, prognosis

8 9

INTRODUCTION

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Cardiac resynchronization therapy (CRT) is an established therapeutic option for systolic

11

heart failure concomitant with electrical dyssynchrony.1-4 The extent of baseline electrical

12

dyssynchrony is currently determined by prolongation of the QRS duration with a left bundle

13

branch block (LBBB) morphology which is a well-known predictor of CRT response.3,4

14

Restoration of the dyssynchronous conduction within the His-Purkinje system by means of

15

biventricular pacing has been proposed as the mechanism of action that correlates with the

16

clinical and echocardiographic improvements after CRT.4,22 Narrowing of the native QRS

17

duration as a marker of reversed electrical remodeling (RER) after CRT has been shown to

18

correlate with favorable structural changes and CRT response in previous studies.21,22

19

Mitral regurgitation (MR), a significant prognostic marker in patients with heart failure

20

has been shown to be reduced by CRT, although the precise mechanisms are not fully

21

understood.5-7 The impact of native QRS narrowing on the degree of MR and on the geometrical

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changes of the mitral valve following CRT have not been addressed previously. The objectives of

2

the present study are 1) To evaluate the relation of CRT-induced RER to the improvement in

3

functional status, CRT response, improvement in MR and in mitral geometry, 2) To test the

4

hypothesis that narrowing of the native QRS duration might predict prognostic outcomes such as

5

reduction in MR severity and decrease in death and hospitalization during follow-up.

6

MATERIAL and METHODS

7

Patient selection and study design

8

A total of 172 patients receiving a biventricular device with or without a defibrillator

9

(CRT-D or CRT-P) was retrospectively analyzed in the study. Compatible with the current

10

guidelines,8 all patients had a left ventricular ejection fraction (LVEF) ≤ 35%, an increased QRS

11

duration (≥120 ms) and symptomatic heart failure (NYHA II-IV) despite optimal medical

12

therapy. Patients with right ventricular pacing upgraded to CRT and those with pace-maker

13

dependency were excluded. Patients with organic MR defined as moderate to severe annular

14

calcifications, rheumatic valve disease, mitral valve prolapse with or without flail leaflet/chordae,

15

and a history of mitral valve repair or replacement were excluded.9 Patients with inadequate

16

image quality to calculate left ventricular (LV) volumes (n= 12) and those with trivial mitral

17

regurgitation that precluded the quantification of MR (n= 44) were also excluded from the

18

analyses. Patients who failed to continue follow-up visits (n=6) were excluded leading to a final

19

study population consisted of 110 CRT recipients with MR. The study protocol was approved by

20

the local ethics committee and written informed consent was obtained from all participants.

21

ECG recordings

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Baseline, post-implantation (paced) and follow-up intrinsic (when the CRT device was

2

switched-off) 12-lead ECG tracings were recorded on a chart paper at a speed of 50 mm/sec with

3

a gain setting of 10 mm/mV. QRS duration was defined as the widest interval in any of the 12

4

leads. QRS duration was manually measured and double-checked with the computer output.

5

Baseline QRS morphologies were recorded as either LBBB or non-LBBB based on the well-

6

defined criteria.12 Paced QRS intervals were calculated after echocardiographic device

7

optimization which was performed during the hospital stay. At 6 months of follow-up, CRT

8

devices were switched-off for 10 seconds to assess the native conduction. The intrinsic QRS

9

duration on the follow-up ECG was included in the study data to determine RER which was

10

defined as narrowing of the native QRS duration after CRT.

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Device implantation and programming

12

Transvenous approach via the left subclavian vein was used to implant CRT-D or CRT-P

13

devices under local anesthesia in the vast majority of patients. The right atrial lead was located in

14

the right atrial free wall (in patients with sinus rhythm) and the right ventricular lead was located

15

in the right ventricular apex or the outflow tract according to the operator’s choice. Following a

16

coronary sinus angiography, the LV lead was inserted preferably in the postero-lateral vein as

17

recommended.10 In case of anatomic difficulties for implanting the LV lead in the optimal

18

position (in 12 patients), minimal invasive surgical approach was preferred to implant an

19

epicardial LV lead. Use of a defibrillator lead depended on the clinical indication or the

20

operator’s choice. Initial device programming was performed by setting default values of 100

21

msec for the sensed AV interval, 130 msec for the paced AV interval, and 20 msec for the VV

22

interval (LV preceding RV). Both AV and VV intervals were checked before patient discharge

23

and optimized with a previously described echocardiographic method in case of necessity.11 The

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ECG obtained after optimization was used to measure the paced QRS duration to include in the

2

study data.

3

Echocardiographic analyses

4

Baseline and 6-month follow-up echocardiography were performed with a commercially

5

available system (Vivid E9, General Electric, Milwaukee, USA) using a 3.5 MHz transducer. The

6

cine-loops for measurements of LV volumes, mitral deformation indices and MR quantification

7

were recorded in the left lateral decubitus position. Offline analysis was performed by two expert

8

sonographers who were blinded to the study data.

9

LV measures

10

Apical two- and four-chamber views were used to calculate LV volumes both in end-

11

systole (LVESV) and end-diastole (LVEDV); once obtained, the results were used to calculate

12

the left ventricular ejection fraction (LVEF) using the biplane Simpson’s method.13

13

Mitral valve deformation and quantification of MR

14

Mitral geometry was assessed in the parasternal long-axis view at mid-systole. Tenting

15

area (TA) was measured as the area enclosed between the annular plane and the coaptation point

16

of the mitral leaflets.14 Tenting distance (TD) was measured as the perpendicular line between the

17

annular plane and the coaptation point of the mitral valve leaflets.14 The change in TA at 6

18

months compared to baseline was defined as delta-TA (ΔTA).

19

Proximal iso-velocity surface area (PISA) method was used to determine the severity of

20

mitral regurgitation, as described previously.15 MR was quantified as the effective regurgitant

21

orifice area (EROA) and the regurgitant volume (RegV). Depending on the change in RegV at 6

22

months, patients were either defined as MR responders (RegV reduced at follow-up) or MR non-

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responders (no change or increase in RegV) at 6 months. The change in RegV at 6 months

2

compared to baseline was defined as delta-RegV (ΔRegV).

3

Reproducibility

4

Twenty randomly-selected patients were retrospectively re-evaluated to test the

5

reproducibility of the main echocardiographic parameters in the study. Intra-observer variability

6

was found as 8% and inter-observer variability as 9% for measuring RegV, while these values

7

were respectively found as 5% and 8% for measuring LVESV, all of which were within a

8

clinically acceptable range.

9

Follow-up and definition of outcomes

10

The end-points of the study were designated as all-cause-death and heart failure related

11

hospitalization. Patients were followed-up for a mean period of 18 ± 3 months (range: 1 to 24)

12

beginning from the day of CRT. Regular clinical visits were scheduled for intervals of 3 months.

13

The follow-up data were obtained through regular visits, by telephone calls, and from hospital

14

records. Only one event was counted for each patient during the follow-up.

15

Improvement in functional status was defined as ≥ 1 grade decrease in NYHA class at 6

16

months of follow-up. Response to CRT was defined as a ≥ 15% reduction in LVESV at 6 months.

17

Improvement in MR (MR response) was defined as absolute reduction in RegV at 6 months

18

compared to baseline. The study population (n=110) was divided into two groups based on

19

narrowing of the intrinsic QRS interval (RER) assessed at 6 months: patients without RER

20

(n=62) and patients with RER (n=48). Both groups were compared in terms of the baseline

21

clinical, ECG and echocardiographic features, as well as the outcome variables defined as

22

functional improvement, CRT response, MR response, death and hospitalization.

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Statistical analyses

2

Statistical analyses were conducted using SPSS (version 17.0, SPSS Inc., Chicago, IL,

3

USA). Data were expressed as mean ± SD for continuous variables and percentage for categorical

4

variables. Shapiro-Wilk test was used to test for normal distribution. Continuous variables were

5

compared using Student’s t-test for independent samples that showed normal distribution, while

6

the Mann-Whitney U test was used for non-normally distributed samples based on RER.

7

Associations of the categorical variables between groups were tested using Chi-square test.

8

Comparison of the baseline and the follow-up values for the NYHA class, intrinsic QRS duration,

9

and several echocardiographic parameters according to the status of RER was performed by

10

paired-sample t-test and the results were shown with a table. Statistical significance was defined

11

as a p value < 0.05 for all comparisons. Pearson’s correlation analysis was used to test the

12

relationship between 1) the change in intrinsic QRS duration and the change in RegV at 6 months

13

and 2) the change in intrinsic QRS duration and the change in TA. The results of the correlations

14

were shown on separate scatted-dot graphs with the corresponding r and p values.

15

Cox proportional hazard models were separately created to determine the predictors of all-

16

cause death and combined death/hospitalization after CRT. By univariate analysis, variables

17

showing significant differences with outcome (p < 0.05) were included in the multivariate

18

analysis. Baseline QRS duration, LBBB morphology, paced QRS duration, follow-up intrinsic

19

QRS duration, and RER (a positive ΔQRS) were the independent variables to predict outcome.

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Time variables were defined as the time to death and time to death or hospitalization in months.

21

The results of the Cox regression were reported as hazard ratio (HR), 95% confidence limits, and

22

p-values in a table.

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Univariate and multivariate logistic regression analyses were performed in order to define

2

the independent predictors of MR improvement after CRT. Statistically significant (p < 0.05)

3

variables in the univariate analysis were tested in the multivariate model. Baseline QRS duration,

4

paced QRS duration, follow-up intrinsic QRS duration, RER, baseline LVEF, baseline LVESV,

5

and TA were the independent variables, whereas the MR response was the dependent variable of

6

the model. Results of the regression analyses were expressed as the p value and odds ratio (OR)

7

in confidence interval of 95% and demonstrated with a table.

8

Kaplan-Meier curves were generated to analyze the effect of RER on survival and event-

9

free survival during the time course of the study. Each analysis was demonstrated with a separate

10

graphic and the results were expressed as Log rank and p values.

11

RESULTS

12

The study population had a mean age of 64 ± 11 (36% female), mean LVEF of 26.5 ±

13

5.7% and mean baseline QRS duration of 160.5 ± 20.9 milliseconds. Overall, 48 patients (44%)

14

had RER defined as narrowing of the intrinsic QRS duration assessed while CRT was switched

15

off at 6 months. Comparison of the baseline features of the study population based on RER was

16

shown in Table 1. In general, two groups were comparable except for the aetiology of heart

17

failure and the paced QRS durations after CRT. Patients with RER were more likely to have non-

18

ischemic cardiomyopathy (60% vs. 55%, p= 0.032) and had shorter paced QRS durations (149.3

19

± 20.1 ms vs. 160.6 ± 26.5 ms, p= 0.012) compared to patients without RER.

20

Overall, the end-point of all-cause death was reached in 17 patients (4 patients with RER

21

vs. 13 patients without RER) and combined death/hospitalization was observed in 43 patients (12

22

patients with RER vs. 31 patients without RER) during the mean follow-up of 18 ± 3 months

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(range 1-24). A total of 71 patients (65%) responded to CRT, and MR improvement was

2

observed in 58 patients (53%) at 6 months.

3

Table 2 demonstrates the baseline and the CRT-induced changes in echocardiographic

4

parameters (including LVESV, LVEDV, LVEF, EROA, RegV, TA and TD), as well as the

5

change in severe functional status (NYHA III/IV) and intrinsic QRS duration in the overall

6

population and in groups based on RER. Reduction in NYHA III/IV status and improvements in

7

and LV volumes/function were observed in the overall population and in both RER groups.

8

However, parameters of MR quantification (EROA and RegV) and mitral geometry (TA and TD)

9

seemed to improve only in patients with RER and worsen in patients without RER (all p values <

10

0.05). The overall population had a minor reduction in MR and slight improvement in mitral

11

geometry which did not reach to a statistical significance.

12

Functional improvement in RER groups

13

The association of the improvement in NYHA class based on RER was demonstrated on

14

Figure 1A. Functional improvement was observed more frequently in patients with RER (n= 37

15

vs. n= 21), whereas patients without RER were more likely to have NYHA class unchanged or

16

worsened (n=41 vs. n= 11) after CRT (Pearson Chi-square = 20.268, p < 0.001). In addition,

17

although the baseline mean NYHA classes were similar (2.9 ± 0.6 vs. 2.8 ± 0.7, p= 0.683),

18

patients with RER showed a significant functional improvement (follow-up NYHA classes: 1.9 ±

19

0.7 vs. 2.5 ± 0.9, p= 0.002) compared to patients without RER at 6 months.

20

Association of RER with LV reverse remodeling

21

Comparison of the LV remodeling parameters in RER groups revealed that although the

22

mean baseline LVESV values were similar (157.7 ± 49.8 ml vs. 156.4 ± 51.4 mL, p= 0.865),

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follow-up mean LVESV values were significantly lower (132.6 ± 47.5 ml vs. 143.8 ± 53.6 mL,

2

p= 0.025) and the mean change in LVESV were significantly higher (25.0 ± 15.4 mL vs. 12.5 ±

3

23.1 mL, p= 0.002) in patients with RER (Supplemental Figure 1A). Similarly, mean baseline

4

LVEF values were comparable (26.0 ± 5.8% vs. 27.2 ± 5.4%, p= 0.280) but mean follow-up

5

LVEF was significantly lower (28.1 ± 7.4% vs. 32.0 ± 6.9%, p= 0.007) and the mean change in

6

LVEF was higher (4.7 ± 3.8% vs. 2.1 ± 5.4%, p= 0.005) in patients with RER compared to

7

patients without RER (Supplemental Figure 1B). The relationship between CRT response and

8

RER was demonstrated with a clustered bar chart in Figure 1B revealing that presence of RER

9

was associated with CRT response, whereas the absence of RER was associated with CRT non-

10

response (Pearson Chi-square= 10.384, p< 0.001).

11

Impact of RER on MR severity and mitral geometry

12

A total of 58 patients (44 patients with RER vs. 14 patients without RER) were found to

13

have reduction in RegV at 6 months, whereas 52 patients (4 patients with RER vs. 48 patients

14

without RER) had no change or increase in MR after CRT (Pearson Chi-square= 24.163, p<

15

0.001) as shown in Figure 1C. The extent of change in the native QRS duration compared to the

16

baseline QRS duration (ΔQRS) showed a significant linear correlation with the change in RegV

17

(ΔRegV) (r= 0.513, p < 0.001) and the change in TA (ΔTA) (r= 0.349, p< 0.001) following CRT

18

(Supplemental Figure 2A and 2B).

19

Predictors of prognosis and MR improvement

20

Among the several electrocardiographic parameters tested in the univariate Cox

21

proportional hazard model for prediction of survival; statistically significant variables (p values <

22

0.05; paced QRS duration and RER) were entered in the multivariate analysis to determine the

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independent predictors. RER (HR= 1.026, 95% CI= 1.014 – 1.039, p= 0.043) was found to

2

independently predict all-cause death. In order to define the independent predictors of combined

3

death/hospitalization, statistically significant variables in the univariate model (baseline QRS

4

duration, paced QRS duration, and RER) were tested by multivariate Cox’s regression. Paced

5

QRS duration (HR= 1.012, 95% CI= 1.005 – 1.019, p= 0.048) and RER (HR= 2.071, 95% CI=

6

1.208 – 4.910, p= 0.028) independently predicted event-free survival during the overall follow-up

7

(Table 3).

8

Table 4 demonstrates the logistic regression analyses for prediction of reduction in RegV

9

(MR response) after CRT. Significant variables (p< 0.05) in the univariate model (paced QRS

10

duration, RER, baseline LVESV and baseline TA) were entered in the multivariate analysis. RER

11

(hazard ratio= 1.103, 95% confidence interval= 1.007 – 1.208, p= 0.023) and baseline TA (hazard

12

ratio= 2.011, 95% confidence interval= 1.268 – 2.754, p= 0.014) were the independent predictors

13

of MR improvement after CRT.

14

Estimation of survival and event-free survival based on RER were separately analyzed by

15

Kaplan-Meier method as shown in Figure 2A and 2B. Presence of RER showed statistical

16

significance for prediction of survival (free from all-cause death, Log rank: 3.938, p=0.047) and

17

event-free survival (free from combined death/hospitalization, Log rank: 6.066, p=0.014) during

18

the mean follow-up of 18 ± 3 months after CRT.

19

DISCUSSION

20

In the current study, we evaluated the clinical impact of narrowing of the intrinsic QRS

21

duration after CRT on the echocardiographic and clinical outcomes. According to the main

22

findings of the study, a narrowed intrinsic QRS duration compared to the baseline was strongly

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associated with higher incidence of functional improvement, greater CRT response and reduced

2

MR severity. Moreover, narrowing of the native QRS duration was a predictor of MR response,

3

hospitalization, and death during the follow-up.

4

CRT has been primarily accepted as an electrical therapy that aims to restore the

5

synchronicity of the conduction system in the failing heart.16 The evidence arising from the RV-

6

pacing studies17 supports that deterioration of intraventricular conduction by inducing iatrogenic

7

LBBB further affects LV systolic dysfunction and can be reversed by biventricular pacing.18

8

Besides, complete restoration of the electrical remodeling in a patient with LBBB resulted in

9

super-response to CRT as shown by Dizon et al.19 suggesting that reversal of electrical

10

remodeling is the main target of biventricular pacing in heart failure.

11

CRT-induced reversal of electrical remodeling has been addressed in several previous

12

studies. Narrowing of the intrinsic QRS duration by CRT was mostly evaluated for favorable

13

structural changes and prediction of CRT response. Although Stockburger and colleagues did not

14

found any association between structural and electrical remodeling20, a study from Boriani et al.

15

suggested that the extent of QRS shortening by CRT was a determinant of reduction in LVESV.21

16

Similarly, Yang et al found that narrowing of the intrinsic QRS complex correlated with CRT

17

response.22 However, there is no uniform definition of RER in the literature. Tereshenko et al.

18

accepted ≥ 10 milliseconds of QRS narrowing as an index of RER and found association with

19

decreased mortality.23 A study from Yang et al. suggested that regression of the fragmented QRS

20

complex interval was associated with improved electrical conduction that resulted in beneficial

21

outcomes after CRT.24 We observed that even minor alterations in the native QRS duration

22

correlated with significant echocardiographic changes after CRT. Therefore, we used the absolute

23

QRS narrowing as an index of RER to correlate with clinical outcomes in the present study.

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Consistent with the recent studies, our study once again confirmed that the presence of

2

RER is strongly associated with increased functional and echocardiographic response after CRT.

3

However, we investigated the effect of RER beyond the extent of LV reverse remodeling. We

4

also correlated RER with important prognostic variables such as improvement in MR and

5

reduction in death and hospitalization. Reversal of the intrinsic electrical dyssynchrony induced

6

by CRT is the suggested mechanism of action that triggers the reversal of both mechanical

7

dyssynchrony and LV remodeling leading to favorable clinical and echocardiographic outcomes

8

after CRT.

9

Comparison of the baseline characteristics in our study population revealed that

10

traditional CRT response predictors25 such as female gender, baseline QRS duration and LBBB

11

morphology did not differ in RER groups. However, patients with RER had non-ischemic

12

cardiomyopathy more frequently and tended to have narrower paced QRS durations which may

13

have influenced the results of the study. According to a previous report by Hsing et al.26, paced

14

QRS and the CRT-induced QRS change predicted favourable clinical outcomes and LV reverse

15

remodelling. Similarly, QRS narrowing as indexed to baseline was significantly associated with

16

reversed LV remodeling after CRT as reported by Rickard et al.18 Lecoq and colleagues

17

evaluated CRT response in 139 patients and noted that QRS narrowing was a determinant of CRT

18

response.3 We achieved similar results in our study regarding the importance of paced QRS

19

duration after CRT. Based on the regression analyses, paced QRS duration was found as a

20

univariate predictor of both death/hospitalization and MR response that necessitates further

21

studies to confirm these findings.

22

In line with the major CRT trials, we had an overall CRT response rate of 65%. Both the

23

overall population and the RER groups showed marked reduction in mean NYHA class and

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marked improvements in LV remodeling parameters (LVESV, LVEDV and LVEF). In contrast,

2

reduction in MR severity and improvement in mitral valve geometry were observed solely in the

3

group of patients with RER. The MR parameters assessed in the study (RegV, EROA, TA and

4

TD) significantly worsened in patients without RER, while mildly (statistically insignificant)

5

improved in the overall population. Overall, 58 patients (53%) were MR responders that

6

consisted of 44 patients with RER and 14 patients without RER. Corresponding MR response

7

rates were 92% vs. 23% in the RER groups that clarified the role of intrinsic QRS narrowing on

8

MR severity after CRT.

9

Predictors of MR improvement after CRT have been widely investigated recently. It is

10

important to differentiate functional MR from organic or ischemic MR both of which involve

11

distinctive mechanisms. CRT has been shown to positively interact with and ameliorate the

12

imbalance between the tethering forces (due to papillary muscle dyssynchrony and/or annular

13

dilatation) and the impaired closing forces (due to reduced LV contractility and/or LV

14

dyssynchrony) that were suggested as the underlying mechanisms of MR in patients with heart

15

failure. Ypenburg et al reported that baseline LV mechanical dyssynchrony was associated with

16

improvement in MR after CRT.7 Sitges et al. suggested that excessive remodeling of the LV and

17

mitral valve predicted an unfavorable MR response after CRT.6 Likewise, we found that baseline

18

LVESV was a univariate predictor of MR response, while baseline TA was an independent

19

predictor of MR response at multivariate analysis. Since previous studies did not provide

20

sufficient data regarding the influence of intrinsic QRS narrowing on MR improvement, our

21

study is among the first to focus on the correlation of ΔQRS with the reduction in RegV and in

22

TA. Moreover, CRT-induced RER has never been suggested as a predictor of MR response

23

previously.

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According to the results of the present study, favorable effects of CRT on MR

2

improvement in patients with RER might be explained by several mechanisms. First,

3

amelioration of the native conduction after CRT results in improvement in LV remodeling

4

parameters that subsequently leads to a decrease in MR severity as a result of smaller LV

5

volumes. Second, improvements in global LV remodeling in patients with RER might favorably

6

interact with the local remodeling parameters acting on the mitral apparatus such as reduction in

7

the mitral annular area, TA, and TD. Third, reversal of the mechanical dyssynchrony, especially

8

at the papillary muscle level is a mechanism for MR improvement after CRT induced by the

9

reversal of the intrinsic electrical dyssynchrony.

10

Among the predictors of death and hospitalization following CRT, we achieved some

11

‘classic’ and ‘novel’ results in the current study. By univariate analysis, traditional variables27-29

12

including the baseline and the paced QRS durations tended to effect prognosis after CRT as

13

expected. These findings were in line with previous meta-analyses investigating the predictors of

14

mortality and morbidity after CRT.30, 31 A unique feature of our study is that narrowing of the

15

intrinsic QRS duration after CRT to be proposed as an independent predictor of both survival and

16

event-free survival by multivariate analysis.

17

Limitations

18

The main limitation of the study is that the study population consists of patients treated in

19

a single center with a relatively small sample size. The overall follow-up period was 18 ± 3

20

months with a wide variation (1 to 24 months) to reach the study end-points. Therefore,

21

assessment of functional improvement, CRT response and MR reduction was done at 6 months

22

which is a generally accepted time interval to assess clinical and echocardiographic response to

23

CRT. Patients who died within the first 6 months (n=3, 1 with RER and 2 without RER) were

Page 16 of 29

17 1

included in the analyses with their baseline values. Besides, the absence of long-term

2

echocardiographic data and that of the association with prognosis during the overall follow-up

3

might also be an issue of criticism.

4

Any method for quantification of MR involves some drawbacks. Although the addition of

5

vena contracta and jet area assessment would have increased the accuracy, the PISA method that

6

we used in the present study to assess RegV is the gold standard by the current guidelines. In

7

addition, three-dimensional assessment by tenting volume analysis would be more precise since

8

the evaluation of the mitral valve remodeling is anatomically challenging. Another possible

9

limitation is that there was a significant overlap between the patients with reduction in the paced

10

and the native QRS durations. The differentiation of a co-existence or a cause-effect relationship

11

must be established in further studies. Finally, long-term clinical data on ventricular arrhythmias

12

or need for transplant/assist device would be more comprehensive since we only focused on

13

major clinical end-points such as improvement in NYHA class, hospitalization and death.

14

CONCLUSION

15

Reversed

electrical

remodeling

by

means

of

narrowing

of

the

intrinsic

16

electrocardiographic QRS duration after CRT has clinical and prognostic implications. A

17

narrowed intrinsic QRS interval than the baseline is associated with improved functional status,

18

higher CRT response, reduced MR and favorable prognosis after CRT. The results of the present

19

study suggest that the assessment of the native conduction should be a part of routine clinical

20

follow-up of patients after CRT. Further randomized studies are needed for translation of our

21

findings into clinical practice with algorithms including RER assessment for early prediction of

22

prognosis after CRT.

Page 17 of 29

18 1 2

FUNDING: None-declared.

CONFLICT OF INTEREST: None-declared.

3 4 5 6 7 8

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20. Stockburger M, Nitardy A, Fateh-Moghadam S, Krebs A, Celebi O, Karhausen T, Dietz R.

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Electrical remodeling and cardiac dimensions in patients treated by cardiac resynchronization

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and heart failure controls. Pacing Clin Electrophysiol. 2008 Jan;31(1):70-7. doi:

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21. Boriani G, Biffi M, Martignani C, Ziacchi M, Saporito D, Grigioni F, Domenichini G,

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23. Tereshchenko LG, Henrikson CA, Stempniewicz P, Han L, Berger RD. Antiarrhythmic effect

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27. Hsu JC, Solomon SD, Bourgoun M, McNitt S, Goldenberg I, Klein H, Moss AJ, Foster E;

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MADIT-CRT

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resynchronization therapy and associated improvement in clinical outcome: the MADIT-CRT

21

(multicenter automatic defibrillator implantation trial with cardiac resynchronization therapy)

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study. J Am Coll Cardiol. 2012 Jun 19;59(25):2366-73. doi: 10.1016/j.jacc.2012.01.065.

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29. Upadhyay GA, Chatterjee NA, Kandala J, Friedman DJ, Park MY, Tabtabai SR et al.

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Assessing mitral regurgitation in the prediction of clinical outcome after cardiac

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resynchronization therapy. Heart Rhythm. 2015 Feb 20. pii: S1547-5271(15)00201-5. doi:

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30. Sipahi I, Chou JC, Hyden M, Rowland DY, Simon DI, Fang JC. Effect of QRS morphology

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on clinical event reduction with cardiac resynchronization therapy: meta-analysis of

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10.1016/j.ahj.2011.11.014.

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31. Cleland JG, Abraham WT, Linde C, Gold MR, Young JB, Claude Daubert J, Sherfesee L,

14

Wells GA, Tang AS. An individual patient meta-analysis of five randomized trials assessing

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the effects of cardiac resynchronization therapy on morbidity and mortality in patients with

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symptomatic

17

10.1093/eurheartj/eht290.

heart

failure.

Eur

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Dec;34(46):3547-56.

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18 19

Supplemental Figure 1. Box-plots presenting the association of RER with LV remodeling

20

parameters and CRT response at 6 months. 1A: Baseline (left panel) mean LVESV values were

21

similar among the RER groups (p= 0.865), while patients with RER had a significantly lower

22

follow-up (right panel) mean LVESV values (p= 0.025). 2B: RER groups had a similar baseline

Page 23 of 29

24 1

(left panel) mean LVEF (p= 0.280), but the mean LVEF (p= 0.007) was significantly higher in

2

patients with RER at 6 months (right panel).

3 4

Supplemental Figure 2. Association of RER with MR severity and mitral geometry after CRT.

5

2A: Change in the native QRS duration (ΔQRS) was significantly correlated with the change in

6

RegV (ΔRegV) at 6 months of follow-up (r= 0.513, p< 0.001). 2B: Correlation of ΔQRS with the

7

change in tenting area (ΔTA) at 6 months (r= 0.349, p < 0.001).

8 9

FIGURE LEGENDS

10

Figure 1. Bar charts demonstrating the association between reverse electrical remodeling (RER)

11

and functional/echocardiographic/MR response at follow-up. 1A: Functional response (≥1 degree

12

improvement in NYHA class) was observed more frequently in patients with RER, while patients

13

without RER seemed to have a worsened or unchanged NYHA class (p < 0.001). 1B: CRT

14

response was more frequently observed in patients with RER, whereas CRT non-response was

15

more pronounced in patients without RER (p < 0.001). 1C: MR response (reduction in RegV)

16

was more frequently observed in patients with RER, while patients without RER seemed to have

17

worsened or unchanged FMR at 6 months (p< 0.001).

18 19

Figure 2. Kaplan-Meier curves generated for estimation of the study end-points during a mean

20

follow-up of 18 ± 3 months. 2A: Estimation of the survival (free from all-cause death, Log

21

Rank= 3.938, p= 0.047). 2B: Estimation of the event-free survival (free from combined

22

death/hospitalization, Log Rank= 6.066, p= 0.014).

Page 24 of 29

25 1

Table 1. Comparison of the baseline demographic, clinical and electrocardiographic features of

2

the study population according to the narrowing of the intrinsic QRS duration following CRT

3

represented as RER (-) or RER (+). Overal

RER (-)

RER (+)

(n=110)

(n = 62)

(n =48)

66 (61 – 75)

64 (58 – 71)

67 (62 – 73)

0.096

36% (40)

35% (22)

38% (18)

0.829

BSA (/m2) *

1.86 (1.73 – 1.99)

1.89 (1.73 – 1.99)

1.83 (1.72 – 2.02)

0.795

BMI (kg/m2)

27.5 ± 4.7

27.3 ± 4.6

27.7 ± 5.0

0.699

Non-ischemic etiology % (n)

57% (63)

55% (34)

60% (29)

0.032

Hypertension % (n)

73% (80)

68% (42)

75% (36)

0.124

Diabetes % (n)

33% (36)

37% (23)

27% (13)

0.271

Hyperlipidemia % (n)

46% (51)

51% (32)

39% (19)

0.074

Atrial fibrillation** % (n)

27% (30)

29% (18)

25% (12)

0.641

NYHA III/IV % (n)

64% (71)

60% (37)

71% (34)

0.229

CRT-D % (n)

89% (98)

87% (54)

92% (44)

0.162

LBBB morphology

85% (94)

83% (51)

89% (43)

0.120

160.5 ± 20.9

158.8 ± 21.8

162.7 ± 19.6

0.326

65% (71)

60% (37)

71% (34)

0.225

155.9 ± 25.0

160.6 ± 26.5

149.3 ± 20.1

0.012

Hb (g/dL)

12.4 ± 1.6

12.3 ± 1.8

12.7 ± 1.4

0.232

Cr (mg/dL) *

1.0 (0.9 – 1.3)

0.9 (0.8 – 1.4)

1.0 (0.9 – 1.3)

0.429

Age (years) * Female gender % (n)

Baseline QRS duration (ms) QRS ≥ 150 ms, % (n) Paced QRS duration (ms)

p value

Medication % (n) Beta-blocker

95% (104)

94% (58)

96% (46)

0.605

ACE-I / ARB

96% (105)

95% (59)

96% (46)

0.868

Page 25 of 29

26 Spironolactone

76% (84)

74% (46)

79% (38)

0.241

Furosemide

82% (90)

82% (50)

81% (40)

0.442

Digoxine

40% (44)

42% (26)

37% (18)

0.136

Nitrate

28% (31)

31% (19)

25% (12)

0.347

Amiodarone

36% (40)

35% (22)

38% (18)

0.229

Oral anti-coagulation ***

25% (28)

27% (17)

23% (11)

0.162

1

*: Median (Interquartile range, Q1 – Q3), BSA: Body surface area, BMI: Body mass index, NYHA: New York Heart

2

Association, CRT-D: Biventricular device combined with a defibrillator, LBBB: Left bundle branch block, Hb:

3

Hemoglobin, Cr: Creatinine, ACE-I: Angiotensin converting enzyme inhibitor, ARB: Angiotensin receptor blocker.

4

**: Chronic or paroxysmal atrial fibrillation. ***: Warfarin or novel agents (dabigatran, apixaban or rivaroxaban)

Page 26 of 29

27 1TaTable 2. Change in functional status, ECG and echocardiographic parameters in overall population and in groups based on reverse electrical remodeling.

Overall (n = 110)

RER (-) (n = 62)

RER (+) (n = 48)

Baseline

Follow-up

p value

Baseline

Follow-up

p value

Baseline

Follow-up

p value

64% (71)

35% (38)

0.014

60% (37)

45% (28)

0.031

71% (34)

21% (10)

0.002

Intrinsic QRS (ms)

160.5 ± 20.9

161.6 ± 21.3

0.242

158.8 ± 21.8

166.6 ± 21.3

< 0.001

162.7 ± 19.6

155.0 ± 19.7

< 0.001

LVESV (mL)

157.0 ± 50.5

138.9 ± 51.1

< 0.001

156.4 ± 51.4

143.8 ± 53.6

< 0.001

157.7 ± 49.8

132.6 ± 47.5

< 0.001

LVEDV (mL)

212.6 ± 57.9

197.4 ± 56.9

< 0.001

209.1 ± 57.5

198.8 ± 57.7

0.001

217.1 ± 58.7

195.6 ± 56.4

< 0.001

LVEF (%)

26.5 ± 5.7

29.8 ± 7.4

< 0.001

26.0 ± 5.8

28.1 ± 7.4

0.003

27.2 ± 5.4

32.0 ± 6.9

< 0.001

EROA (cm2)

0.24 ± 0.14

0.23 ± 0.11

0.162

0.22 ± 0.11

0.29 ± 0.15

0.001

0.21 ± 0.11

0.16 ± 0.10

0.001

RegV (mL)

30.7 ± 17.3

29.1 ± 14.8

0.276

28.9 ± 15.0

36.5 ± 18.5

< 0.001

29.5 ± 14.6

22.2 ± 12.1

< 0.001

TA (cm2)

3.98 ± 0.85

3.95 ± 0.86

0.709

3.7 ± 0.7

3.8 ± 0.8

0.029

4.3 ± 0.8

3.9 ± 0.9

0.004

TD (cm)

2.0 ± 0.4

1.9 ± 0.4

0.788

1.9 ± 0.4

2.0 ± 0.4

0.032

2.0 ± 0.5

1.9 ± 0.4

0.010

NYHA III/IV, % (n)

2 3

RER: Reverse electrical remodeling, NYHA: New York Heart Association, LVESV: Left ventricular end-systolic volume, LVEDV: Left ventricular end-diastolic

4

volume, LVEF: Left ventricular ejection fraction, EROA: Effective regurgitant orifice area, RegV: Regurgitant volume, TA: Tenting area, TD: Tenting distance.

5 6 7 8

Page 27 of 29

28 1

Table 3. Cox proportional hazard model for prediction of all-cause mortality and combined death and

2

hospitalization by univariate and multivariate analyses

Univariate Analysis

Multivariate Analysis

HR

95% CI

p value

HR

95% CI

p value

Baseline QRS duration

0.987

0.963 – 1.011

0.272

LBBB morphology

0.658

0.189 – 2.293

0.511

Paced QRS duration

1.033

1.012 – 1.054

0.036

0.456

0.085 – 2.440

0.359

Follow-up intrinsic QRS duration

1.000

0.979 – 1.021

0.641

Reverse electrical remodeling

2.180

1.356 – 3.504

0.026

1.026

1.014 – 1.039

0.043

Baseline QRS duration

1.125

1.082 – 1.168

0.012

0.842

0.416 – 1.706

0.112

LBBB morphology

1.430

0.755 – 2.709

0.272

Paced QRS duration

1.026

1.014 – 1.039

0.022

1.012

1.005 – 1.019

0.048

Follow-up intrinsic QRS duration

0.996

0.983 – 1.010

0.587

Reverse electrical remodeling

2.245

1.150 – 4.382

0.018

2.071

1.208 – 4.910

0.028

Death from all cause

Combined death and hospitalization

3 LBBB: 4 Left bundle branch block, CRT: Cardiac resynchronization therapy, MR: Mitral regurgitation, HR: Hazard ratio, CI: Confidence 5 interval.

6 7

Page 28 of 29

29 1

Table 4. Univariate and multivariate logistic regression analyses to determine the independent

2

predictors of improvement in mitral regurgitation (MR response).

Univariate Analysis OR

95% CI

p value

Baseline QRSd

1.009

0.991 – 1.028

0.318

Paced QRSd

1.040

1.023 – 1.057

0.032

Follow-up intrinsic QRSd

1.044

0.977 – 1.117

0.201

Reverse electrical remodeling

2.651

1.112 – 6.309

0.032

Baseline LVESV

1.012

1.005 – 1.019

0.028

Baseline LVEF

0.767

0.327 – 1.798

0.541

Tenting Area

1.916

1.228 – 2.290

0.012

Multivariate Analysis OR

95% CI

p value

Paced QRSd

0.996

0.985 – 1.007

0.415

Reverse electrical remodeling

1.103

1.007 – 1.208

0.023

Baseline LVESV

1.966

0.410 – 9.428

0.398

Tenting Area

2.011

1.268 – 2.754

0.014

3 4

QRSd: QRS duration, LVESV: Left ventricular ejection fraction, LVEF: Left ventricular ejection fraction, OR:

5

Odds ratio, CI: Confidence interval.

6 7

Page 29 of 29