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Impact of Right Ventricular Apical Pacing and Its Frequency on Left Atrial Function

Background Right ventricular apical (RVA) pacing induces left ventricular (LV) dyssynchrony, increases the risk of persistent atrial fibrillation in the long term. The aim was to investigate the effects of RVA pacing on left atrial (LA) function, which are unknown. Methods Echocardiographic evaluation including LV dyssynchrony based on conventional Doppler, tissue Doppler imaging and speckle tracking strain echocardiography was done before and after (12 months) single-chamber ventricular pacemaker implantation in 40 patients with sick sinus syndrome. Patients were divided to 2 groups, according to the RVA pacing frequency (group I had higher pacing rate of more than 50% and group II, less than 50%). Results There was no significant difference in LV ejection fraction, however, mean global LV strain, myocardial performance index, and parameters of LV dyssynchrony had shown significant changes after 12 months of RVA pacing. There were also significant increase in the LA volume index and the reduction of peak systolic LA strain and strain rate (SR), peak early and late diastolic SR after RVA pacing. Moreover, there was significant deterioration of LV dyssynchrony and both LA and LV longitudinal function in even group II. LA functional deterioration and LA volume was significantly correlated with the frequency of RVA pacing. Conclusion LV dyssynchrony, induced by RVA pacing, significantly impaired active LA contraction and passive stretching, and these findings were shown in the patients with even less than 50% of RVA pacing. Impairment of LA strain/SR was significantly correlated with the frequency of RVA pacing.


Introduction
Right ventricular apical (RVA) pacing, independently of pacing mode, can create an artificial inter-ventricular conduction delay and impairs left ventricular (LV) function. 1) Several large, randomized clinical trials on pacing mode selection have suggested an association between a high percentage of RVA pacing and increased risks of atrial fibrillation (AF) and heart failure in patients with sick sinus syndrome (SSS). [2][3][4] Longterm RVA pacing may also result in changes in LV wall thickness 5) and LV remodeling such as degenerative fibrosis. 6)7) In addition, functional mitral regurgitation and left atrial (LA) remodeling may occur during RVA pacing. 8)9) However, it remains unclear whether the deterioration of LA function, as noted in a proportion of patients receiving RVA pacing, is directly related to LV dyssynchrony. Since assessment of myocardial longitudinal function based on strain echocardiography may be a sensitive marker for detecting subclinical alterations in LV and LA systolic performance, [10][11][12] we assessed the impact of chronic RVA pacing on LA function using tissue Doppler based strain echocardiography and association of LA strain parameters with LV mechanical dyssynchrony in the present study. We also aimed to know that patients can have significant myocardial functional benefit from lower frequency of RVA pacing compared with higher frequency of pacing.

Study design and subjects
We prospectively observed 40 patients who needed permanent pacemaker implantation for SSS between March 2008 and October 2010. The study population consisted of singlechamber ventricular pacemaker (VVI mode) because of technical difficulties for the other types of pacemaker including dual chamber, and right ventricular outflow track pacing pacemakers. No patients had a history of ischemic heart disease, AF, bundle branch block, moderate to severe valvular heart disease, and systolic heart failure (LV ejection fraction < 50%).
Pacemaker follow-up was done at 1, 3, 6, and 12 months after implantation. The participants were divided into 2 groups according to the mean RVA pacing frequency (group I had higher pacing rate of more than 50% and group II, less than 50%), and echocardiographic variables as below were analyzed, as well. The study protocol was approved by the Institutional Review Committee on Human Research at Maryknoll Medical Center, and informed consent was obtained from all study subjects before participation.

Echocardiographic evaluation
A standard 2-dimensional and strain echocardiographic examination using a 2.5-MHz transducer on the Vivid 7 Dimension ultrasound equipment (General Electric, Horten, Norway) was performed on all subjects before and after (12 months) pacemaker implantation during normal sinus rhythm not ventricular pacing as possible.

Standard and Doppler echocardiography
Measurement of LV volume, LA volume and ejection fraction was calculated by the Simpson's methods from the apical 4-and 2-chamber views. Pulsed wave (PW) Doppler of transmitral LV inflow was performed in the apical 4-chamber view, with the sample volume placed at the level of the mitral valve tips and Doppler variables were analyzed during 3 consecutive beats. The following parameters of global LV diastolic function were determined: peak early (E) and late (A) diastolic mitral flow velocity and their ratio (E/A), early (Ea) diastolic mitral annular velocity, deceleration time of the E wave, and LV isovolumic relaxation time (IVRT). Doppler time intervals were measured from mitral inflow and LV outflow velocity-time intervals as described by Tei et al. 13) and the index of combined LV systolic and diastolic function (myocardial performance index) was calculated from the sum of isovolumic contraction time and IVRT divided by ejection time.

Strain echocardiography
Speckle tracking strain imaging (frame rate ≥ 70/sec) and tissue Doppler strain imaging (TDI, frame rate ≥ 115/sec) was performed in the apical 2-chamber, 3-chamber, and 4-chamber views using a narrow sector angle. Images from apical chamber views of the LV were obtained at end-expiratory apnea and were stored in cine-loop format for subsequent offline analysis. Three heartbeats were collected from each view and a selected 1-cycle was analyzed off-line with an EchoPAC Dimension system (General Electric, Horten, Norway).
Peak longitudinal systolic strains were measured and averaged to assess global longitudinal myocardial regional function. The endocardial borders were traced at the end-systolic frame, and an automated tracking algorithm outlined the myocardium in successive frames throughout the cardiac cycle. The tracking quality was verified for each segment (with subsequent manual adjustment of the region of interest, if necessary), and myocardial motion was analyzed by speckle tracking within the region of interest bound by endocardial and epicardial borders. Inadequate tracked segments were automatically excluded from analysis. In this situation, local strain in each segment was calculated. Global LV strain was obtained by averaging all segment strain values from the apical 4-chamber, 2-chamber, and long axis views.
For the LA strain, longitudinal peak strain and strain rate were obtained from 2 different areas of the basal segments of the LA free wall and the inter-atrial septum in the apical 4 chamber view by the tissue Doppler strain. For the longitudinal measurements, a computation area of 9 × 2 mm with an elliptical shape was chosen, 12) and mean peak systolic LA strain and strain rate (Sm-SR), peak early diastolic strain rate (Em-SR) and late diastolic strain rate (Am-SR) are measured.

Measurements of dyssynchrony
The inter-ventricular mechanical delay, calculated as difference between left pre-ejection interval (LPEI) and right preejection interval (RPEI). LPEI is measured by PW Doppler in apical long axis projection and RPEI in short axis parasternal projection with sample volume in level of aortic (LPEI) or pulmonary (RPEI) valve. LPEI and RPEI is the interval from QRS beginning to start of ejection flow. 14) For the intra-ventricular dyssynchrony, myocardial velocity curves are analyzed by tissue synchronization imaging in the apical 2-chamber, 3-chamber, and 4-chamber views. Using the 6-basal, 6-midsegmental LV model, the time from the onset of the QRS complex to peak systolic velocity in ejection period (Ts) are measured in each segment with 12 × 6 mm sample volume. The septal-to-lateral delay (Ts-SL), a TDI index proposed by Bax et al., 15) is measured as the difference of Ts between the basal septal and lateral walls. The septal-toposterior delay (Tε-SP) is measured as the time difference from the onset of the QRS complex and peak systolic radial strain wave between the anteroseptum and posterior walls at the parasternal short axis view by speckle tracking strain imaging. 16) Parameters of intra-ventricular dyssynchrony are calculated from Ts-SL or from the standard deviation of Ts (Ts-SD) among the 12 LV segments or Tε-SP.

Statistical analysis
Statistical analysis was performed with SPSS 15.0 package program (IBM Corp., Armonk, NY, USA). Results are presented as mean ± standard deviation. Paired Student's t-test was used for comparisons of continuous variables between be-fore and after RVA pacing. Comparisons of all measurements were made with independent t-test for the parameters be-tween group I and II. Correlations between variables were assessed by Pearson correlation, and p value of less than 0.05 was considered statistically significant. Table 1 lists baseline characteristics of the 40 patients with SSS. The study population included 15 men and 25 women, with a mean age of 65.3 ± 10.2 years (range, 58-86 years). Twenty three patients had hypertension, 7 had diabetes mellitus, and 20 had dyslipidemia. Twenty one patients were on calcium-channel blockers, and 23 on angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. The range of ventricular pacing frequency was 7.8-99.2%. Table 2 showed the echocardiographic variables before and after 12 months of single-chamber ventricular RVA pacing. Although there was no significant change in LV volume and ejection fraction, the LV mass index, E/Ea, and LA volume index were significantly increased after RVA pacing. Also, there were significantly increased myocardial performance index Values are means ± SDs. RVA: right ventricular apical, LV: left ventricular, Ts: the time from the onset of the QRS complex to peak systolic velocity in ejection period, Ts-SL: the difference of Ts between the basal septal and lateral walls, Ts-SD: the standard deviation of Ts among the 12 LV segments, Tε-SP: the time difference from the onset of the QRS complex and peak systolic radial strain wave between the anteroseptum and posterior walls, LA: left atrial, E: peak early diastolic mitral flow velocity, A: peak early diastolic mitral flow velocity, Ea: peak early diastolic mitral annular velocity, Sm-SR: mean peak systolic strain rate, Em-SR: peak early diastolic strain rate, Am-SR: peak late diastolic strain rate and reduced global LV strain after RVA pacing as well as increased intra-ventricular delays of both TDI velocity and strain analysis ( Table 2). The values of the peak systolic LA strain and Sm-SR, Em-SR and Am-SR were also significantly reduced after 12 months of RVA pacing.

Long-term effects of RVA pacing on echocardiographic parameters
Comparison of long-term effects of cumulative ventricular pacing percent on echocardiographic parameters Table 3 showed the changes of the echocardiographic parameters before and after pacing in both groups. Average pacing frequency was undoubtedly different (group I: 89.4 ± 12.5 vs. group II: 25.9 ± 20.7%, p < 0.001). After pacing, the values of LV mass index and LA volume index were significantly higher in the group I, which was not demonstrated in the group II. However, there were significant differences in the value of global LV strain, myocardial performance index and intra-ventricular delays of both TDI velocity and strain analysis before and after RVA pacing in both group I and even in the group II (smaller pacing frequency group) (Table 3). Also, there were significantly increased E/Ea and reduced peak systolic LA srain, Sm-SR, Em-SR and Am-SR before and after RVA pacing in both group I and the group II (Table 3). Interestingly, there was significant difference in the intra-ventricu-lar delays of both TDI velocity and strain analysis in favor of group II (Ts-SD; group II 40.2 ± 16.9 ms vs. group I 51.7 ± 14.7 ms, p = 0.025, Tε-SP; group II 46.6 ± 26.7 ms vs. group I 52.9 ± 24.5 ms, p = 0.003). Moreover, group I showed significantly lower global LV strain (-12.5 ± 4.92 vs. -15.9 ± 5.97%, p = 0.023) and peak LA systolic strain (28.2 ± 11.6 vs. 37.1 ± 10.4%, p = 0.012) compared with group II.

Correlation between the frequency of RVA pacing and the echocardiographic variables of LA function
There were significant correlations between the frequency of RVA pacing and the representative parameters of LA function, except for Ts-SD, and Em-SR (Table 4). Interestingly, the peak LA strain showed significant negative correlation with the pacing percentage (r = -0.425, p=0.028) ( Table 4).

Discussion
Our study demonstrated that RVA pacing produce LV dyssynchrony and deterioration of LA and LV longitudinal function, as well. Moreover, there was significant reduction of LA and LV function even with lower frequency of RVA pacing, which might be more deteriorated with increased LV dyssynchrony induced by high frequency of RVA pacing. Values are means ± SDs. RVA: right ventricular apical, LV: left ventricular, Ts: the time from the onset of the QRS complex to peak systolic velocity in ejection period, Ts-SL: the difference of Ts between the basal septal and lateral walls, Ts-SD: the standard deviation of Ts among the 12 LV segments, Tε-SP: the time difference from the onset of the QRS complex and peak systolic radial strain wave between the anteroseptum and posterior walls, LA: left atrial, E: peak early diastolic mitral flow velocity, A: peak early diastolic mitral flow velocity, Ea: peak early diastolic mitral annular velocity, Sm-SR: mean peak systolic strain rate, Em-SR: peak early diastolic strain rate, Am-SR: peak late diastolic strain rate

LV functional change by RVA pacing and mechanical dyssynchrony
Animal studies have revealed dramatic mechanical effects from asynchronous electrical activation because the various regions differ not only in the time of onset of contraction but also in the pattern of contraction. 17) Early contracting regions close to the pacing site stretch remote regions that are not yet activated. This stretching further delays shortening of the lateactivation regions. In clinical practice, RVA pacing therapy for bradycardia causes increase in heart failure and AF incidence through LV dyssynchrony. [18][19][20][21] Mechanical dyssynchrony is impacted by the myocardial architecture, not only electrophysiological but also histological and molecular factors. Therefore, it is speculated that the presence of different degrees of myocardial injury and interstitial fibrosis in different myocardial layers and segments of the failing heart would result in heterogeneous conduction abnormalities, which may increase its likelihood of developing mechanical dyssynchrony.
Echocardiographic strain imaging has been shown to be a useful tool to assess regional LV function, and useful to evaluate the effects of mechanical dyssynchrony on LV function because it can differentiate active thickening from passive wall motion. Our result shows the reduced global LV strain after 12 months RVA pacing indicating deterioration of LV systolic deformation as a result of asynchronous electrical activation by RVA pacing. Moreover, unexpectedly, reduced global LV strain was found even in the lower frequency of RVA pacing after 12 months, as well.

LA functional change by RVA pacing and mechanical dyssynchrony
Atrial function during early diastole is strongly influenced by the LV compliance, 22) and atrial function as reservoirs during systolic period is influenced by atrial relaxation. Booster pump function during late diastole is the intrinsic atrial contraction. LA dysfunction will be present even in a stage with slightly elevated LA pressure, and parameters of LA contractility assessed by conventional Doppler echocardiography are augmented in this stage; thus it will be difficult to detect LA dysfunction by this method. Our study shows similar mitral inflow filling patterns with non-significant increase in augmentation of late diastolic A velocity with RVA pacing.
The atrial walls consist of intricately intermingled muscular bundles oriented circumferentially and longitudinally 23) with individual contractility. TDI, as it measures myocardial velocities, displacement and deformation, has been shown to be less load-dependent regional quantitative parameters that reflect regional contraction and relaxation. 24) To date, not much data is available on atrial myocardial velocities, and our previous studies showed the role of values of LA strain/SR in diagnosis and management in patients with AF. 12)25) We chose to measure the TDI-based LA strain from the basal segments of the inter-atrial septum and the LA lateral wall, because it moves in a direction more parallel to the ultrasound beam and it is less affected by LV motion and translation. Analysis of the TDI-based LA strain demonstrated no significant difference in the septal wall and lateral wall. In this study, we found that there was significant increase in the LA volume index with increased E/Ea after RVA pacing, which implicating increased LV filling pressure. Moreover, the values of the peak systolic LA strain and Sm-SR, Em-SR and Am-SR were significantly reduced with RVA pacing. The possible mechanism is that the RVA pacing may increase inter-ventricular dyscoordination and LV depolarization times and consequently, the transmitral inflow during early diastole is compromised, which causes a larger residual volume before LA contraction. The presence of such volumetric changes and increased LA pressure might reduce longitudinal deformation, so the atrial lengthening that occurs during ventricular ejection is significantly reduced, and the atrial shortening that occurs during ventricular early filling is also reduced. Other studies have shown that LA pressure and volume overload resulted in significant RVA: right ventricular apical, LA: left atrial, CI: confidence interval, Ts: the time from the onset of the QRS complex to peak systolic velocity in ejection period, Ts-SL: the difference of Ts between the basal septal and lateral walls, Ts-SD: the standard deviation of Ts among the 12 LV segments, Tε-SP: the time difference from the onset of the QRS complex and peak systolic radial strain wave between the anteroseptum and posterior walls, E: peak early diastolic mitral flow velocity, Ea: peak early diastolic mitral annular velocity, Sm-SR: mean peak systolic strain rate, Em-SR: peak early diastolic strain rate, Am-SR: peak late diastolic strain rate up-regulation of beta-myosin heavy chain in the LA body associated with decreased velocity of LA contraction. 26) In our study, the peak systolic LA strain, Sm-SR, Em-SR and Am-SR were reduced by RVA pacing, which implies an impaired passive lengthening (stretching) and shortening of the atrial walls, and this is possibly because of increased residual volume with reduced compliance and increased pressure. Moreover, the reduced LA strain parameters were found even in the lower frequency of RVA pacing after 12 months, as well. However, the significant negative correlation between the frequency of RVA pacing and the peak systolic LA strain/ SR implicate the deterioration of LA function might be exacerbated by high ventricular pacing.

Study limitations
Although we tried to assess LA function by strain echocardiography, LA function also could be evaluated by the phasic volume, so the simultaneous measurement of LA phasic volume and LA strain variables might provide the more accurate LA functional change induced by mechanical dyssynchrony. Secondary, separate measurement of intraventricular and interventricular synchrony index and strain parameters during with narrow QRS and wide QRS would be helpful to know the effect of RVA pacing-induced dyssynchrony or RVA pacing itself on LA. Finally, although we sought to evaluate the pure effect of RVA pacing on myocardial performance, the number of patients was so small. Large scale multicenter trial is definitely necessary to test our results.

Conclusion
After 12 months of single-chamber ventricular pacemaker implantation, significant deterioration of global LV function with LV mechanical dyssynchrony was induced, which may play a role in the development of heart failure. Moreover, LA volume and pressure burden brought by RVA pacing caused an impairment of LA active contraction and passive stretching, assessed by strain echocardiographic parameters, even in the lower pacing percentage group. There were significant correlations between the cumulative percentage of RVA pacing and the representative parameters of LA active contraction and passive stretching, as well.