ORIGINAL RESEARCH

# Mechanism and Impact of Left Atrial Dyssynchrony on Long-Term Clinical Outcome During Cardiac Resynchronization Therapy

<figure><img src="image_1.png" /></figure>

<figure><img src="image_2.png" /></figure>

Lars-Egil R. Hammersboen, MD,ᵃ,ᵇ,ᶜ Marie Stugaard, MD, PHD,ᵃ,ᶜ,>d Alexis Puvrez, MD,ᵉ Camilla K. Larsen, MD, PHD,ᵃ Espen W. Remme, MSc, PHD,ᵃ,f Erik Kongsgård, MD, PHD,ᵇ Jürgen Duchenne, MSc, PHD,ᵉ Elena Galli, MD, PHD,g Faraz H. Khan, MD,ᵃ Ole Jakob Sletten, MD,ᵃ Martin Penicka, MD, PHD,ʰ Erwan Donal, MD, PHD,g Jens-Uwe Voigt, MD, PHD,ᵉ Otto A. Smiseth, MD, PHD,ᵃ,ᵇ,ᶜ John M. Aalen, MD, PHDᵃ,ᵇ

ABSTRACT

**BACKGROUND** Left bundle branch block (LBBB) causes left atrial (LA) dyssynchrony. It is unknown if LA dyssynchrony impacts long-term prognosis.

**OBJECTIVES** The purpose of this study was to determine mechanisms of LA dyssynchrony in LBBB and if LA dyssynchrony impacts long-term prognosis.

**METHODS** In a prospective multicenter study of 168 heart failure patients with LBBB, echocardiographic strain imaging was done before and after 6 months with cardiac resynchronization therapy (CRT). Outcome was assessed after 6 years. Dyssynchrony was measured relative to septum as delay in left ventricular (LV) lateral wall shortening and LA lateral wall stretch. Response to CRT was defined as at least 15% reduction in LV end-systolic volume.

**RESULTS** Before CRT, there was marked LA dyssynchrony of 105 ± 76 ms, which decreased to 37 ± 68 ms in CRT-responders (P < 0.001), whereas nonresponders showed only a modest reduction in LA dyssynchrony (P < 0.05). There was strong association between LA and LV dyssynchrony (r = 0.70), consistent with direct LV-LA mechanical interaction. CRT caused modest increase in LA reservoir strain (P < 0.01) and marked increase of LV filling time (P < 0.001) in responders. Mortality after 6 years was 21% (35 deaths). LA dyssynchrony did not independently predict mortality. However, the combination of preserved LA reservoir strain (≥18%) and resolved LA dyssynchrony (≤53 ms) after 6 months with CRT was associated with excellent long term-prognosis: HR: 0.11 (95% CI: 0.03-0.42) vs preserved reservoir strain and persistent LA dyssynchrony.

**CONCLUSIONS** LA dyssynchrony in LBBB was attributed to direct LV-LA mechanical interactions. CRT improved diastolic function by increasing LV filling time. Patients with preserved LA reservoir strain and resolution of LA dyssynchrony by CRT had excellent long-term prognosis. (Contractile Reserve in Dyssynchrony: A Novel Principle to Identify Candidates for Cardiac Resynchronization Therapy [CRID-CRT]; NCT02525185) (JACC Cardiovasc Imaging. 2025;18:421-432) © 2025 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

From the ᵃInstitute for Surgical Research, Oslo University Hospital, Oslo, Norway; ᵇDivision of Cardiovascular and Pulmonary Diseases, Cardiology Department, Oslo University Hospital. Oslo, Norway; ᶜInstitute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; ᵈVestre Viken Hospital Trust, Ringerike, Norway; ᵉUniversity Hospitals (UZ) Leuven, Department of Cardiovascular Sciences, Leuven, Belgium; ᶜThe Intervention Center, Oslo University Hospital, Oslo, Norway; ᵈLaboratory Signal Processing and Image, Department of Cardiology, Rennes, France; and the ᵇCardiovascular Center Aalst, OLV Clinic, Aalst, Belgium.
ABBREVIATIONS
AND ACRONYMS

AF = atrial fibrillation

CRT = cardiac
resynchronization therapy

GLS = global longitudinal
strain

HF = heart failure

ICC = intraclass correlation
coefficient

LA = left atrial

LARS = left atrial reservoir
strain

LBBB = left bundle branch
block

LV = left ventricular

Over the last several years, parameters of left atrial (LA) function have emerged as strong predictors of morbidity and mortality in patients with heart failure (HF),¹,² including those with left bundle branch block (LBBB) undergoing cardiac resynchronization therapy (CRT).³ In addition to beneficial effects on cardiac remodeling measured as reductions in left ventricular (LV) and LA volumes, CRT leads to improvement in left atrial reservoir strain (LARS).⁴⁻⁶ As suggested by a retrospective single-center study, improvement in LARS provides incremental prognostic value since a combination of LARS and LV global longitudinal strain (GLS) was superior to GLS alone as predictor of long-term outcome.⁷ Because LARS is closely related to LV filling pressure,⁸ its incremental prognostic value during CRT may just reflect an association between severity of HF and prognosis. It is not known if correction of LA dyssynchrony by CRT has independent prognostic value, and, if so, by which mechanism. Because the LA plays an important role in LV filling, a potential mechanism of beneficial effect could be improvement in LV filling after synchronization of atrial myocardial segments.

The objectives of the present study were to investigate mechanisms of LV-LA interactions during LBBB and to determine if resolution of LA dyssynchrony by CRT is associated with beneficial long-term prognosis.

METHODS

**STUDY POPULATION.** A total of 236 HF patients referred for CRT were prospectively included from Oslo University Hospital, Norway (n = 101), University Hospitals Leuven, Belgium (n = 50), Rennes University Hospital, France (n = 71), OLV Hospital Aalst, Belgium (n = 11), and Karolinska University Hospital, Sweden (n = 3) between August 2015 and November 2017.⁹ Inclusion criterion was indication for CRT according to 2013 European Society of Cardiology guidelines.¹⁰ Exclusion criteria included recent myocardial infarction, recent cardiac surgery, and severe aortic stenosis. In the present study, we excluded 68 patients due to inadequate echocardiographic image quality for atrial strain analysis (n = 23), lack of echocardiographic data (n = 11), CRT

not implanted (n = 24), study withdrawal (n = 4), lead extraction due to endocarditis (n = 1), or death or transplantation before follow-up (n = 5). LBBB was defined according to 2013 European Society of Cardiology guidelines.¹⁰ The present patient population was also part of our previous publication on LA strain during CRT.⁴

To rule out reduced LV function as a cause of LA dyssynchrony, we also included 20 patients with nonischemic cardiomyopathy with QRS duration <130 ms from another recently published study.¹¹

Both the study on CRT and the one on patients with QRS duration <130 ms were approved by regional ethics committees and written, informed consent was obtained from all study participants. The CRT study was registered at clinicaltrials.gov (NCT02525185).

**ECHOCARDIOGRAPHY.** Echocardiography (Vivid E9 or E95 scanner, GE Vingmed Ultrasound AS, Horten, Norway) was performed before and 7 ± 1 month after CRT implantation. Recordings included 2-dimensional grey-scale images from LV apical views for speckle-tracking echocardiography of the LA and LV. LA and LV volumes were obtained using the biplane Simpson's method. All volumes were indexed to body surface area. LV filling time was measured as time from opening to closure of the mitral valve on 2-dimensional grey-scale apical images.

**ANALYSIS AND CALCULATION OF REGIONAL STRAIN VALUES AND TIMING OF EVENTS.** LA and LV longitudinal strain were measured using speckle-tracking echocardiography using the Q-module for LV strain analysis in EchoPAC v203 (GE Vingmed Ultrasound AS, Horten, Norway) and reported as absolute values.

The LA wall was traced in the apical 4-chamber view along the endocardial border by defining the region of interest from the septal mitral annulus to the lateral mitral annulus, extrapolating across the pulmonary veins and the LA appendage orifices. LARS was calculated from LV-end diastole and LA pump strain after onset of the p-wave in the electrocardiogram at the sharp downslope of the strain trace, as recommended in the American Society of Echocardiography/European Association of Cardiovascular Imaging consensus report and most recent expert statement.¹²,¹³

Zero-reference for timing of onset stretch in the LA was set at the time for onset segmental systolic
shortening in the LV, using whichever segment started shortening first. Values of timings and strain from the interatrial septum and LA lateral wall were calculated as the mean of the basal and mid segments. Differences in values were calculated as absolute differences of means. The roof segments were excluded.

For the LV, the septal and lateral wall was traced using single wall analysis in the apical 4-chamber view. The strain curve representing the mean of the basal, mid, and apical segments automatically calculated in EchoPAC was used for measurements. Reverse LV remodeling was defined as at least 15% reduction in LV end-systolic volume at 6 (7 ± 1) months follow-up and was used to define CRT response.

**DEFINITIONS.** LA dyssynchrony. The time delay between onset systolic stretch of the interatrial septum and the LA lateral wall (Central Illustration).

**LA reservoir phase duration.** Measured from onset systolic shortening in the LV to peak global LA strain.

**LA strain amplitudes.** Defined as the difference between minimum and peak strain during the reservoir phase.

**LA strain nonuniformity.** Defined as lateral wall-septal strain amplitude difference.

**LV dyssynchrony.** Defined as the time delay between onset shortening in the interventricular septum and the LV lateral wall. Onset shortening was measured at the sharp downslope of the strain trace after onset QRS.

**CRT IMPLANTATION.** Patients underwent standard implantation of a biventricular pacing system. Coronary venography was used to optimize placement of the LV lead in a lateral or posterolateral vein. The device was programmed in a conventional biventricular pacing modus and retested before hospital discharge.

**STATISTICAL ANALYSIS.** Estimates are presented as CIs and remaining continuous variables as mean ± SD. Comparisons between 2 groups were performed using the Student's t-test. Univariable and multivariable linear regression analyses were used to explore the relationship between LA dyssynchrony and other parameters. Survival data are presented as Kaplan-Meier curves with log-rank test and HRs (Cox regression). The initiating time-point was the date of CRT implantation, and the ending time-point was date of death or last available follow-up. Cutoff for LARS was set to 18% according to Inoue et al.⁸ Cutoff for LA dyssynchrony and reservoir phase duration was set using receiver operating characteristic curve

analysis, guided by Youden Index using all-cause mortality as endpoint. Bland-Altman plot, Pearson correlation coefficient, and intraclass correlation coefficient (ICC) were used for reproducibility. If not otherwise stated, *P* < 0.05 was considered significant. IBM SPSS Statistics (Windows, Version 26.0, IBM Corp) was used for all statistical analysis.

**REPRODUCIBILITY.** Intraobserver and intercenter (Oslo and Leuven) variability for LA and LV dyssynchrony and LARS were studied in 10 randomly selected patients before and after CRT.

## RESULTS

Baseline characteristics are summarized in Table 1. During 6 months of follow-up, 118 of 168 patients (70%) underwent LV reverse remodeling and were considered CRT responders. Before CRT, responders had significantly lower LA volume index and trended toward higher LARS compared with nonresponders. There were no significant differences in LV functional and volumetric parameters. During follow-up, absolute GLS and LARS increased and LA volume index decreased in responders, whereas in nonresponders there were no significant changes (Table 2).

**MECHANISM OF LA DYSSYNCHRONY.** The Central Illustration show that LA reservoir phase strains are opposite to and coincide with active LV contractions, indicating a direct LV/LA mechanical interaction. Thus, in the normal subject shown in Central Illustration A, LA strain is a mirror image of LV strain, and in the LBBB patient, the early septal contraction coincides with early stretch of the interatrial septum. During LV systole, there are intraventricular wall interactions with corresponding strains in the interventricular septum and lateral wall. When the late-activated LV lateral wall contracts, however, there is corresponding stretch of the LA lateral wall.

The result of these LV/LA interactions is marked LA reservoir phase dyssynchrony with large time difference between onset stretch of the interatrial septum and the LA lateral wall. After 6 months with CRT, however, LV contractions are largely synchronized and LA dyssynchrony is abolished. The findings are illustrated in Central Illustration, B and in Videos 1 and 2. Parallel LV and LA resynchronization also occurred shortly after CRT before LV remodeling had occurred, as shown in the representative example in Supplemental Figure 1.

For the entire patient group there was marked LA dyssynchrony of 105 ± 76 ms before CRT, which was reduced to 43 ± 69 ms at 6 months of follow up (*P* < 0.001). Similarly, LV dyssynchrony was
**CENTRAL ILLUSTRATION** CRT Improves LA Function Through Direct Ventriculoatrial
Mechanical Interactions

**A Mechanism of LA Dyssynchrony: Attributed to LA Tethering to a Dyssynchronous LV**

<figure><img src="image_3.png" /></figure>

**B CRT Resynchronizes the LA and LV**

<figure><img src="image_4.png" /></figure>

**C CRT Improves LA Function in Responders**

<figure><img src="image_5.png" /></figure>

Hammersboen L-ER, et al. JACC Cardiovasc Imaging. 2025;18(4):421-432.

(A) The mechanism for LA dyssynchrony during reservoir phase was attributed to LA tethering to a dyssynchronous LV. The normal individual in A is from a previous study.¹¹ (B) Before CRT, there was LA dyssynchrony, which was abolished by CRT in parallel with LV resynchronization.

(C) Positive response to CRT was associated with resynchronization of the LA and improved LA function. In the box plots, the central lines indicate the mean and the upper and lower edges the SD. 2D = 2-dimensional; CRT = cardiac resynchronization therapy; ECG = electrocardiogram; LA = left atrial; LBBB = left bundle branch block; LV = left ventricular.
126 ± 59 ms (*P* < 0.001) before CRT and markedly reduced to 37 ± 65 ms during follow-up (*P* < 0.001). LA and LV dyssynchrony were similarly present in the subgroup of patients with atrial fibrillation (AF) during echocardiographic examination (n = 11).

Univariable regression analysis revealed a direct relation between LA and LV dyssynchrony (*r* = 0.70; *P* < 0.001) (Central Illustration A) and between LA and LV resynchronization (*r* = 0.56; *P* < 0.001). In multivariable analysis including GLS and electrocardiogram markers of dyssynchrony (QRS morphology and QRS width), LV dyssynchrony was the only significant determinant of LA dyssynchrony (*P* < 0.001) (Table 3).

There was no significant LA or LV dyssynchrony in the patients with nonischemic cardiomyopathy and narrow QRS.

**LA DYSSYNCHRONY, CRT RESPONSE, AND LV FILLING.**
In CRT responders, reduction in LA dyssynchrony was substantially larger than in nonresponders (70 ± 99 ms vs 32 ± 94 ms; *P* < 0.05) (Figure 1, Table 2). LA dyssynchrony before CRT was significantly associated with LV reverse remodeling after CRT in univariable analysis (*r* = 0.27; *P* < 0.001). However, in multivariable analysis including predictors of CRT response like LV dyssynchrony, QRS duration, and QRS morphology, LA dyssynchrony was not independently associated with LV reverse remodeling (*P* = 0.068) (Table 4). Furthermore, there was no significant correlation between change in LA dyssynchrony and change in LV stroke volume.

**Figure 2** illustrates the effects of CRT on LV systolic filling time in a representative responder and **Table 2** shows mean data. After CRT, LV systolic duration is markedly reduced, thus providing more time for LV filling. Correspondingly, the LA reservoir phase duration is reduced, allowing for more time for LA emptying before onset active LA contraction. In nonresponders, however, there was only a small numerical reduction in LA reservoir phase duration (*P* = 0.117). In addition, there was a small improvement in LARS in responders (from 19% ± 8% to 21% ± 9%; *P* = 0.006), but no significant change in non-responders (17% ± 9% to 15% ± 10%; *P* = 0.325).

There were no changes in LA pump strain in either responders or nonresponders.

As shown in **Table 2**, with CRT, there was improvement in E, e' septal, E/e' septal, E/e' average, and LA volume index.

<table><caption>**TABLE 1** Baseline Characteristics</caption><thead><tr><th></th><th>All Patients<br>(N = 168)</th><th>Responders<br>(n = 118)</th><th>Nonresponders<br>(n = 50)</th><th>P Value</th></tr></thead><tbody><tr><td>Age, y</td><td>67 ± 11</td><td>68 ± 11</td><td>64 ± 12</td><td>0.024</td></tr><tr><td>Male</td><td>70</td><td>64</td><td>84</td><td>0.008</td></tr><tr><td>Weight, kg</td><td>79 ± 15</td><td>76 ± 14</td><td>86 ± 17</td><td>&lt;0.001</td></tr><tr><td>HF etiology</td><td></td><td></td><td></td><td></td></tr><tr><td>Nonischemic</td><td>67</td><td>75</td><td>48</td><td>&lt;0.001</td></tr><tr><td>Ischemic</td><td>33</td><td>25</td><td>52</td><td>&lt;0.001</td></tr><tr><td>Medication</td><td></td><td></td><td></td><td></td></tr><tr><td>ACEI/ARB</td><td>97</td><td>97</td><td>96</td><td>0.714</td></tr><tr><td>Beta-blocker</td><td>90</td><td>89</td><td>94</td><td>0.314</td></tr><tr><td>Aldosterone antagonists</td><td>39</td><td>39</td><td>38</td><td>0.905</td></tr><tr><td>Diuretic agents</td><td>69</td><td>68</td><td>72</td><td>0.593</td></tr><tr><td>Rhythm</td><td></td><td></td><td></td><td></td></tr><tr><td>Sinus</td><td>82</td><td>84</td><td>76</td><td>0.195</td></tr><tr><td>AF</td><td>7</td><td>5</td><td>10</td><td>0.254</td></tr><tr><td>Paced</td><td>11</td><td>10</td><td>16</td><td>0.500</td></tr><tr><td>LBBB QRS complex morphology</td><td>88</td><td>91</td><td>82</td><td>0.114</td></tr><tr><td>QRS duration, ms</td><td>166 ± 19</td><td>169 ± 20</td><td>159 ± 17</td><td>0.003</td></tr><tr><td>Upgrades</td><td>18</td><td>14</td><td>28</td><td>0.038</td></tr><tr><td>Systolic blood pressure, mm Hg</td><td>125 ± 21</td><td>126 ± 21</td><td>121 ± 19</td><td>0.154</td></tr><tr><td>Diastolic blood pressure, mm Hg</td><td>70 ± 11</td><td>70 ± 12</td><td>69 ± 10</td><td>0.495</td></tr><tr><td>NYHA functional class</td><td>2.3 ± 0.6</td><td>2.3 ± 0.5</td><td>2.4 ± 0.6</td><td>0.312</td></tr><tr><td>Mitral regurgitation, 0-3</td><td>1.2 ± 0.8</td><td>1.2 ± 0.8</td><td>1.3 ± 0.9</td><td>0.405</td></tr></tbody></table>

Values are % or mean ± SD, unless otherwise indicated. Groups compared using independent-samples Student's t-test (2-tailed).

ACEI = angiotensin-converting enzyme inhibitor; AF = atrial fibrillation; ARB = angiotensin II receptor blocker; HF = heart failure; LBBB = left bundle branch block.

**LA STRAIN AND LONG-TERM OUTCOME AFTER CRT.**

After a median follow-up of 5.8 ± 1.8 years, 35 (21%) patients had died. The number of deaths in responders and nonresponders were 16 (14%) and 19 (38%), respectively. LARS was significantly lower (15% ± 9% vs 20% ± 10%; *P* = 0.003) and LA dyssynchrony numerically higher (61 ± 68 ms vs 39 ± 69 ms; *P* = 0.099) in patients who died compared with survivors. As shown in **Figure 3**, LARS after CRT was independently associated with long-term all-cause mortality (log-rank *P* < 0.05). The HR for LARS <18% vs LARS ≥18% was 2.1 (95% CI: 1.1-4.0; *P* < 0.05).

LA dyssynchrony after CRT was not independently associated with mortality. However, in patients with LARS ≥18% after CRT, resolution of LA dyssynchrony defined as values ≤53 ms identified patients with particularly excellent long-term survival (HR: 0.11; 95% CI: 0.03-0.42; *P* < 0.01 vs patients with reservoir strain ≥18% and LA dyssynchrony >53 ms) (Figure 4B). Patients with low LARS <18% had similar outcome regardless of LA dyssynchrony. There were
<table><caption>TABLE 2 Parameters of Atrial and Ventricular Function and Dyssynchrony</caption><thead><tr><th rowspan="2"></th><th colspan="2">All Patients<br>(N = 168)</th><th colspan="2">Responders<br>(n = 118)</th><th colspan="2">Nonresponders<br>(n = 50)</th></tr><tr><th>Baseline</th><th>6 Mo Follow-Up</th><th>Baseline</th><th>6 Mo Follow-Up</th><th>Baseline</th><th>6 Mo Follow-Up</th></tr></thead><tbody><tr><td>Heart rate, beats/min</td><td>66 ± 12</td><td>66 ± 11</td><td>67 ± 12</td><td>65 ± 11</td><td>64 ± 14</td><td>67 ± 12</td></tr><tr><td>LV end-diastolic volume index, mL/m²</td><td>102 ± 35</td><td>86 ± 35<sup>a</sup></td><td>99 ± 35</td><td>76 ± 28<sup>a</sup></td><td>109 ± 34</td><td>112 ± 37<sup>b</sup></td></tr><tr><td>LV end-systolic volume index, mL/m²</td><td>75 ± 30</td><td>53 ± 30<sup>a</sup></td><td>74 ± 30</td><td>42 ± 21<sup>a</sup></td><td>77 ± 29</td><td>79 ± 30<sup>b</sup></td></tr><tr><td>LV stroke volume, mL</td><td>58 ± 19</td><td>64 ± 22<sup>a</sup></td><td>55 ± 19</td><td>63 ± 21<sup>a</sup></td><td>64 ± 20<sup>b</sup></td><td>67 ± 23</td></tr><tr><td>LA volume index, mL/m²</td><td>45 ± 17</td><td>43 ± 18<sup>c</sup></td><td>44 ± 17</td><td>39 ± 16<sup>a</sup></td><td>49 ± 17<sup>d</sup></td><td>51 ± 20<sup>b</sup></td></tr><tr><td>Global LV longitudinal strain, %</td><td>9.4 ± 3.0</td><td>11.5 ± 3.9<sup>a</sup></td><td>9.6 ± 3.0</td><td>12.8 ± 3.5<sup>a</sup></td><td>9.0 ± 3.0</td><td>8.5 ± 2.9<sup>b</sup></td></tr><tr><td>Global LARS, %</td><td>18 ± 8</td><td>19 ± 10</td><td>19 ± 8</td><td>21 ± 9<sup>c</sup></td><td>17 ± 9</td><td>15 ± 10<sup>b</sup></td></tr><tr><td>Global LA pump strain, %</td><td>13 ± 7</td><td>12 ± 7</td><td>14 ± 7</td><td>14 ± 7</td><td>11 ± 6<sup>d</sup></td><td>9 ± 7<sup>b</sup></td></tr><tr><td>E wave, cm/sec</td><td>75 ± 31</td><td>70 ± 28<sup>c</sup></td><td>71 ± 30</td><td>66 ± 25</td><td>84 ± 32</td><td>77 ± 32</td></tr><tr><td>E/A</td><td>1.22 ± 1.38</td><td>1.11 ± 0.79</td><td>1.11 ± 1.47</td><td>0.97 ± 0.63</td><td>1.49 ± 1.12</td><td>1.42 ± 1.03</td></tr><tr><td>e' septal, cm/s</td><td>4 ± 2</td><td>5 ± 2<sup>a</sup></td><td>4 ± 2</td><td>5 ± 2<sup>a</sup></td><td>5 ± 2</td><td>5 ± 2</td></tr><tr><td>e' lateral, cm/s</td><td>7 ± 3</td><td>6 ± 3</td><td>7 ± 3</td><td>6 ± 3</td><td>7 ± 3</td><td>6 ± 3</td></tr><tr><td>E/e' average</td><td>16 ± 10</td><td>14 ± 9<sup>c</sup></td><td>15 ± 8</td><td>13 ± 8<sup>c</sup></td><td>18 ± 12</td><td>16 ± 10<sup>d</sup></td></tr><tr><td>TRV<sub>max</sub> m/s</td><td>2.5 ± 0.6</td><td>2.5 ± 0.4</td><td>2.4 ± 0.6</td><td>2.5 ± 0.35</td><td>2.8 ± 0.6</td><td>2.7 ± 0.4</td></tr><tr><td>LV dyssynchrony, ms</td><td>126 ± 59</td><td>37 ± 65<sup>a</sup></td><td>133 ± 56</td><td>28 ± 60<sup>a</sup></td><td>109 ± 64<sup>d</sup></td><td>58 ± 70<sup>a,d</sup></td></tr><tr><td>LA dyssynchrony, ms</td><td>105 ± 76</td><td>43 ± 69<sup>a</sup></td><td>111 ± 76</td><td>37 ± 68<sup>a</sup></td><td>89 ± 77</td><td>58 ± 70<sup>c</sup></td></tr><tr><td>LA reservoir phase duration, ms</td><td>522 ± 89</td><td>476 ± 85<sup>a</sup></td><td>531 ± 88</td><td>476 ± 86<sup>a</sup></td><td>500 ± 88<sup>d</sup></td><td>477 ± 83</td></tr><tr><td>LV filling time, ms</td><td>449 ± 160</td><td>487 ± 124<sup>c</sup></td><td>422 ± 139</td><td>490 ± 124<sup>a</sup></td><td>513 ± 188<sup>b</sup></td><td>484 ± 124</td></tr></tbody></table>

Values are mean ± SD. *P < 0.001 vs pre CRT. †P < 0.001 vs responders. ‡P < 0.05 vs pre CRT. §P < 0.05 vs responders. Feasibility of measurements was as follows: E wave: 156 patients pre-CRT, 155 during follow-up; e' lateral: 156 pre-CRT, 148 during follow-up; e' septal: 153 pre-CRT, 148 during follow-up; E/A: 138 pre-CRT, 150 during follow-up; E/e' average: 148 pre-CRT, 145 during follow-up; global LV longitudinal strain: 160 pre-CRT, 156 during follow-up; LA pump strain: 151 pre-CRT, 152 during follow-up; LA volume index: 161 pre-CRT, 153 during follow-up; TRV<sub>max</sub>: 126 pre-CRT, 123 during follow-up. CRT = cardiac resynchronization therapy; LA = left atrial; LARS = left atrial reservoir strain; LV = left ventricular; TRV = tricuspid regurgitant velocity.

similar results when replacing LA dyssynchrony with LA reservoir phase duration (Figure 4D).

**REGIONAL LA STRAIN AMPLITUDES AND NONUNIFORMITY OF STRAIN.** Figure 5 shows segmental strain traces in a representative LBBB patient before and during CRT. This patient illustrates marked nonuniformity in strain amplitudes between the interatrial septum and the LA lateral wall during the reservoir phase before CRT (left), which was abolished by CRT (right). For the entire study population, LA strain amplitudes in the interatrial septum and the LA lateral wall before CRT were 19% ± 10% and 24% ± 11%, respectively (P < 0.001). For the quartile of patients with largest LA strain nonuniformity before CRT, strain amplitudes in the interatrial septum and

the LA lateral wall were 16% ± 9% and 34% ± 12%, respectively (P < 0.001). CRT abolished these differences (P = 0.065).

**REPRODUCIBILITY.** Bland-Altman and linear regression plots for intraobserver variability of LA and LV dyssynchrony and LARS are displayed in Supplemental Figure 2. The ICC was 0.92 (95% CI: 0.79-0.97) for LA dyssynchrony and 0.94 (95% CI: 0.84-0.97) for LV dyssynchrony, indicating good reproducibility. The ICC for global reservoir strain was 0.92 (95% CI: 0.79-0.97).

Bland-Altman and linear regression plots for intercenter variability of LA and LV dyssynchrony and LARS are displayed in Supplemental Figure 3. The ICC between the 2 centers was 0.88 (95% CI: 0.71-0.96) for LA dyssynchrony and 0.87 (95% CI: 0.67-0.95) for LV dyssynchrony, indicating good reproducibility. The ICC for global reservoir strain was 0.94 (95% CI: 0.84-0.98).

## DISCUSSION

The demonstration in the present study of a tight coupling between abnormal LA and LV deformations during LBBB supports the idea that LA dyssynchrony is a direct mechanical effect of tethering between respective walls in the 2 chambers. Correction of

<table><caption>TABLE 3 Multivariable Linear Regression Analysis With LA Dyssynchrony as a Dependent Variable</caption><thead><tr><th></th><th>β</th><th>95% CI</th><th>VIF</th><th>P Value</th></tr></thead><tbody><tr><td>Constant</td><td>11.634</td><td></td><td></td><td></td></tr><tr><td>LV dyssynchrony</td><td>0.710</td><td>0.621-0.799</td><td>1.112</td><td>&lt;0.001</td></tr><tr><td>GLS</td><td>-0.495</td><td>-2.418 to 1.428</td><td>1.174</td><td>0.613</td></tr><tr><td>QRS duration</td><td>0.051</td><td>-0.290 to 0.392</td><td>1.032</td><td>0.770</td></tr><tr><td>LBBB vs non-LBBB</td><td>8.202</td><td>-11.888 to 28.292</td><td>1.047</td><td>0.422</td></tr></tbody></table>

GLS = global longitudinal strain; VIF = variance inflation factors; other abbreviations as in Tables 1 and 2.
dyssynchrony by CRT had a beneficial effect on LA function and LV diastolic function as indicated by marked reduction in duration of the LA reservoir phase and increase in LV filling time.

Whereas LA dyssynchrony was not an independent predictor of mortality, the combination of preserved LARS and resolved LA dyssynchrony at 6 months after CRT was associated with excellent long term prognosis. Notably, prediction of long-term survival was similar when preserved LARS was combined with LA reservoir phase duration.

### MECHANISM OF LA RESERVOIR PHASE DYSSYNCHRONY.

Because the LA is anatomically connected to the LV through the mitral ring and fixed to the pulmonary veins, LV longitudinal shortening implies a corresponding stretch of the LA (Figure 6).⁸ Ventriculoatrial mechanical interaction as the cause of LA dyssynchrony was supported by multivariable analysis where LV dyssynchrony was the only significant determinant of LA dyssynchrony. Moreover, the changes in LV and LA dyssynchrony occurred immediately after resynchronization and, hence, were independent of reverse remodeling. Our findings are in agreement with a recent study from Malaescu et al¹⁴ showing that LA and LV deformation are closely coupled as reflected in the strong correlation between atrial and ventricular strain and strain rate curves during the cardiac cycle.

### LA DYSSYNCHRONY, RESPONSE TO CRT, AND LONG-TERM OUTCOME.
CRT response is multifactorial and includes improvement in both LV systolic and diastolic function.¹⁵ In addition to the direct effect of resynchronization on LV systolic function, LV filling may improve with CRT via 2 mechanisms. First, in patients with prolonged PR-interval, CRT can correct atrioventricular dyssynchrony.¹⁶ Second, as demonstrated in the present study, CRT leads to ventricular and atrial resynchronization with improvement of LA reservoir function and prolongation of LV filling time.

Stassen et al⁷ have shown added value of LARS for predicting survival in CRT. As shown in the present study, LA dyssynchrony measured before and after CRT was not independently associated with survival. However, the combination of LA dyssynchrony and LARS after CRT provided added prognostic value. Thus, patients with LA dyssynchrony ≤53 ms after CRT and LARS ≥18% had excellent long-term prognosis.

Furthermore, measuring duration of LA reservoir phase, which decreased with LA resynchronization, allowed for similar risk stratification as measurement of LA dyssynchrony. This is because LA dyssynchrony and global LA reservoir phase duration reflect the

<figure><img src="image_6.png" /><figcaption>FIGURE 1 LA Dyssynchrony Before and After CRT in Responders and Nonresponders</figcaption></figure>

CRT response was associated with marked reduction in LA dyssynchrony (left boxes). In contrast, in CRT nonresponders there was only a modest reduction in LA dyssynchrony (right boxes). The central lines indicate the mean and the upper and lower edges the SD. CRT = cardiac resynchronization therapy; LA = left atrial.

same electromechanical phenomenon. Global LA reservoir phase duration should be feasible and relatively easy to measure clinically because it does not require segmental strain analysis. Nevertheless, larger prospective studies are needed to validate the clinical utility of measuring LA reservoir phase duration or dyssynchrony in CRT patients.

### EFFECT OF LV AND LA DYSSYNCHRONY ON LV FILLING.
As heart rate increases, diastole is abbreviated, and, therefore, LV filling time is abbreviated, which may contribute to elevated LV diastolic pressure in HF patients. Furthermore, because LA dyssynchrony implies prolongation of the LA reservoir phase, there is delay in ejection of the LA reservoir

<table><caption>TABLE 4 Multivariable Linear Regression Analysis With Change in LV ESV Index as a Dependent Variable</caption><thead><tr><th></th><th>β</th><th>95% CI</th><th>VIF</th><th>P Value</th></tr></thead><tbody><tr><td>Constant</td><td>42.703</td><td></td><td></td><td></td></tr><tr><td>LA dyssynchrony</td><td>-0.048</td><td>-0.100 to 0.004</td><td>1.566</td><td>0.068</td></tr><tr><td>LV dyssynchrony</td><td>-0.041</td><td>-0.109 to 0.026</td><td>1.598</td><td>0.231</td></tr><tr><td>QRS duration</td><td>-0.332</td><td>-0.500 to 0.164</td><td>1.042</td><td>&lt;0.001</td></tr><tr><td>LBBB vs non-LBBB</td><td>8.259</td><td>-1.573 to 18.091</td><td>1.021</td><td>0.099</td></tr></tbody></table>

ESV = end systolic volume; other abbreviations as in Tables 1 to 3.
<figure><img src="image_7.png" /><figcaption>**FIGURE 2** Beneficial Effects of CRT on Diastolic Function: Improved Reservoir Strain, Reduced Duration of LA Reservoir Phase and Increased LV Filling Time</figcaption></figure>

During CRT, LV resynchronization results in LA resynchronization with reduced LA reservoir phase duration (brackets in upper panels) in this representative responder. In parallel, there is increased LV filling time (brackets in lower panels).
2D = 2-dimensional; ECG = electrocardiogram; LV = left ventricular; MVC = mitral valve closure; MVO = mitral valve opening; other abbreviations as in **Figure 1**.

<figure><img src="image_8.png" /><figcaption>**FIGURE 3** LARS and Long-Term Survival</figcaption></figure>

LARS after CRT was associated with long-term survival.
LARS = left atrial reservoir strain; other abbreviations as in **Figure 1**.

volume into the LV, which implies less efficient LA function and LV filling.

As we have shown previously, LBBB has little effect on LV diastolic pressures at normal resting heart rates, but during tachycardia LBBB caused marked elevation of LV diastolic pressure.¹⁷ A likely mechanism is abbreviated diastole and, therefore, insufficient time for complete relaxation.¹⁷ The problem is enhanced in failing hearts with impaired LV relaxation, when increased stroke volume during physical exercise needs to cross the mitral valve in a shorter time, and, therefore, a higher LA pressure is needed to accelerate flow, which may cause upstream elevation of pressure with pulmonary congestion. Therefore, the mechanism demonstrated in this study that CRT is associated with increased LV filling time may reflect a beneficial effect of LA and LV resynchronization. Further studies are needed to explore effects of CRT on LV diastolic function.

**LA DYSSYNCHRONY, REGIONAL STRAIN AMPLITUDES, AND ATRIAL ARRHYTHMIAS.** Minor degree of LA dyssynchrony (named mechanical dispersion) has been linked to recurrence of AF after radiofrequency ablation.¹⁸,¹⁹ Furthermore, LBBB was recently shown to be associated with increased risk of developing AF.²⁰ Potentially, LA dyssynchrony may be a driver for development of atrial arrhythmias in CRT patients. Furthermore, excessive LA lateral wall strain amplitudes during the reservoir phase may stimulate atrial adverse remodeling and represent a trigger mechanism for AF in LBBB.²¹ This hypothesis is supported by the finding that improvement of LA function with CRT is associated with lower incidence of AF.²²

**COMPARISON TO PREVIOUS KNOWLEDGE.** We are aware of no previous prospective study on the impact of LA dyssynchrony on long term-prognosis. Observations in a retrospective, single-center study suggest that LA dyssynchrony may have prognostic impact.⁵ That study, however, was limited to 40 patients and had only 9 cardiovascular events. In contrast, the present study is prospective and multicenter, is substantially larger, and includes patients with AF, ischemic cardiomyopathy, and significant mitral regurgitation. Furthermore, it demonstrates the mechanism of LA dyssynchrony in LBBB, the relationship between LA dyssynchrony and LV filling,
<figure><img src="image_9.png" /><figcaption>FIGURE 4 LA Dyssynchrony and Reservoir Phase Duration and Long-Term Survival</figcaption></figure>

The figures show area under the receiver operating characteristic curves and Kaplan-Meier curves for long-term survival after CRT using LARS together with measures of LA dyssynchrony and reservoir phase duration. (A,B) Combination of LARS and LA dyssynchrony. (C,D) Combination of LARS and LA reservoir phase duration. The analysis used LARS ≥18%, LA dyssynchrony ≤53 ms, and LA reservoir phase duration ≤516 ms as cutoffs. Please note that results were essentially similar for LARS combined with LA dyssynchrony and LARS combined with reservoir phase duration. Both combinations identified patients with excellent long-term survival. AUC = area under the curve; other abbreviations as in Figures 1 and 3.
<figure><img src="image_10.png" /><figcaption>**FIGURE 5** Spatial LA Strain Amplitudes Before and After CRT</figcaption></figure>

The panels illustrate that there was marked spatial nonuniformity in strain amplitude between the interatrial septum and the LA lateral wall during the reservoir phase before CRT (left). After CRT, however, the nonuniformity was largely abolished as indicated by the white circles and brackets (right). The strain traces in the lower panels represent the mean of basal and mid-level strain traces from the interatrial septum (red) and the LA lateral wall (blue) shown in the upper panels. Abbreviations as in **Figures 1 and 2**.

<figure><img src="image_11.png" /><figcaption>**FIGURE 6** Segmental Ventriculoatrial Mechanical Interaction</figcaption></figure>

The figure illustrates the close LV-LA segmental coupling of septal (left) and lateral wall (right) myocardial deformation in a representative LBBB patient with typical dyssynchronous LV contractions. As shown, LA segmental strain traces mirror corresponding LV segmental strain traces throughout the cardiac cycle. LBBB = left bundle branch block; other abbreviations as in **Figures 1 and 2**.
and how LA dyssynchrony impacts long-term outcome.

**STUDY LIMITATIONS.** Twenty-three patients (10%) were excluded from the final analysis due to inadequate image quality for atrial strain analysis. As compared with global strain, regional strain analysis is less robust, and even more so for the thin LA than the thicker LV. In the present study, we took special care to optimize tracking and to avoid structures like the LA appendage, pulmonary veins orifices, and fossa ovalis, which may all cause inaccurate strain measurements. As demonstrated in the intercenter analysis, reproducibility was acceptable.

LA dyssynchrony analyses were done without blinding to LV dyssynchrony and CRT response, which could have introduced a bias.

In theory, right atrial pressure, which was not measured, may directly influence LA reservoir phase strains by modifying stretch of the interatrial septum without influencing the LA lateral wall.

## CONCLUSIONS

In the present study we demonstrate that LA dyssynchrony is a mechanical effect of tethering between respective walls in the LV and LA chambers. Correction of dyssynchrony using CRT had a beneficial effect on LA and LV diastolic function measured as marked reduction in LA reservoir phase duration and prolongation of LV filling time, respectively.

LA dyssynchrony was not an independent predictor of mortality. However, the combination of preserved LARS ≥18% and resolved LA dyssynchrony with CRT was associated with excellent long term-prognosis. Results were similar when using preserved LARS in combination with LA reservoir phase duration as prognostic marker. Future studies should

explore if assessment of LA dyssynchrony should be part of the diagnostic work-up when evaluating CRT patients.

**ACKNOWLEDGMENT** The authors thank Study Nurse Kari Melberg for her valuable contributions to the study.

## FUNDING SUPPORT AND AUTHOR DISCLOSURES

Dr Smiseth is co-inventor of "Method for myocardial segment work analysis," has a patent on "Estimation of blood pressure in the heart" and has received 1 speaker honorarium from GE Healthcare. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

**ADDRESS FOR CORRESPONDENCE:** Dr Otto A. Smiseth, Institute for Surgical Research, Division of Cardiovascular and Pulmonary Diseases, Oslo University Hospital, Rikshospitalet N-0027 Oslo, Norway. E-mail: otto.smiseth@gmail.com.

## PERSPECTIVES

**COMPETENCY IN MEDICAL KNOWLEDGE:** LV dyssynchrony due to LBBB and resynchronization by CRT influences LA function by direct ventriculoatrial mechanical interaction.

**COMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS:**

Segmental LA strain analysis using speckle tracking aids in refining the echocardiographic assessment of dyssynchronous HF and may have added value in CRT patients.

**TRANSLATIONAL OUTLOOK:** The present study suggests that assessment of LA dyssynchrony may be part of the echocardiographic evaluation in patients with dyssynchronous HF. However, there is a need for more studies to confirm the added clinical value of measuring LA dyssynchrony.

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**KEY WORDS** cardiac resynchronization therapy, dyssynchrony, heart failure, left atrial strain, left bundle branch block, left ventricular strain

<figure><img src="image_12.png" /></figure>

**APPENDIX** For expanded Methods and Results sections as well as supplemental figures, please see the online version of this paper.