International Journal of Cardiology 176 (2014) 80–85
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Left anterior descending coronary artery flow impaired by right ventricular apical pacing: The role of systolic dyssynchrony Fang Fang a,b,1, Ze-Ning Jin b,1, Hai-Yan Li b,1, Wei-Jun Zhang b, Zhi-An Li b, Ya Yang b, Xiu-Xia Luo a, Zhi-Hua Zhang a, Alex Pui-Wai Lee a, Cheuk-Man Yu a,⁎, John E. Sanderson a a
Division of Cardiology, Department of Medicine and Therapeutics, Institute of Vascular Medicine; Institute of Innovative Medicine; HEART Center; and Li Ka Shing Institute of Health Sciences, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong Beijing AnZhen Hospital, Capital Medical University, China
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Article history: Received 18 February 2014 Received in revised form 26 May 2014 Accepted 24 June 2014 Available online 2 July 2014 Keywords: Left anterior descending artery Right ventricular apical pacing systolic dyssynchrony
a b s t r a c t Introduction: Right ventricular (RV) pacing may affect myocardial perfusion and coronary blood flow; however, it remains unknown whether this is related to systolic dyssynchrony induced by RV pacing. This prospective study was aimed to assess the relationship between dyssynchrony and the changes of coronary blood flow. Methods: Seventy patients with sinus node dysfunction were prospectively enrolled. Coronary flow was evaluated by measuring diastolic velocity time integral (VTI) and duration at the distal-portion of left anterior descending coronary artery (LAD) with transthoracic echocardiography at baseline and follow-up. Systolic dyssynchrony was assessed with tissue Doppler imaging by time standard deviation to peak systolic velocity of 12 left ventricular segments (Ts-SD, cutoff value ≥33 ms). Results: Adequate data for analysis was available from 65 patients. At follow-up (mean follow up time: 127 ± 45 days), LAD velocity-time integral (LAD-VTI: 12.1 ± 4.2 vs. 10.7 ± 4.6 cm, p b 0.001) was decreased and there was deterioration of left ventricular systolic function (left ventricular ejection fraction: 65 ± 7% vs. 62 ± 7%). However, these changes were only detected in those with RV pacing induced systolic dyssynchrony. Significant reduction of LAD-VTI (defined as ≥5%) occurred in 34 (52%) patients which was more prevalent in those with pacing-induced systolic dyssynchrony than those without (85.3% versus 16.1%, χ2 = 31.1, p b 0.001). Though similar at baseline, LAD-VTI was significantly lower in the dyssynchrony group at follow up (p b 0.001). Cox-regression analysis showed that pacing-inducing systolic dyssynchrony [hazard ratio (HR): 3.62, p = 0.009] and higher accumulative pacing percentage (HR: 1.02, p = 0.002) were independently associated with reduction of LAD-VTI. ROC curve demonstrated that accumulative pacing percentage ≥35% was 97% sensitive and 84% specific in revealing significant reduction (area under the curve: 0.961, p b 0.001). Conclusions: RV pacing induced dyssynchrony is associated with reduced coronary flow and this may account for, in part, the deleterious effect of RV pacing on ventricular function over time. © 2014 Published by Elsevier Ireland Ltd.
1. Introduction
Abbreviations: E′, peak myocardial early diastolic velocity of mitral annulus by pulse wave tissue Doppler imaging; LAD, left anterior descending coronary artery; LV, left ventricle/left ventricular; LVEDV, left ventricular end-diastolic volume; LVEF, left ventricular ejection fraction; LVESV, left ventricular end-systolic volume; RV, right ventricular; TAPSE, tricuspid annular plane systolic excursion; TDI, tissue Doppler imaging; Te-SD, standard deviation of the time to early peak myocardial diastolic velocity among the 12 LV segments; Ts-SD, standard deviation of the time to peak myocardial systolic velocity among the 12 LV segments; VTI, velocity-time integral. ⁎ Corresponding author at: Division of Cardiology, Department of Medicine and Therapeutics, Institute of Vascular Medicine, Institute of Innovative Medicine, HEART Center, and Li Ka Shing Institute of Health Sciences, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong. Tel.: +852 2632 3594; fax: +852 2637 5643. E-mail address: [email protected] (C.-M. Yu). 1 All the authors were equally contributed.
http://dx.doi.org/10.1016/j.ijcard.2014.06.037 0167-5273/© 2014 Published by Elsevier Ireland Ltd.
It has become apparent that not only systolic function but also diastolic function could be impaired after long-term pacing even in patients with normal cardiac function, and this has been considered to be related to systolic dyssynchrony induced by the non-physiological conduction during right ventricular apical (RV) pacing [1,2]. Recent studies have shown that RV pacing can lead to regional perfusion defects, reduction of myocardial oxygen consumption as well as cardiac efficiency even in those without pre-existing coronary artery disease [3–5]. Coronary blood flow detected with transthoracic echocardiography that been shown to be disturbed in patients with LBBB; [6] whereas, data are inconclusive with regard to the coronary flow change after RV pacing despite the presence of an iatrogenic LBBB [6–9]. Furthermore, whether the impact of RV pacing on coronary blood flow is related to pacing-induced systolic dyssynchrony has not been elucidated. This is
F. Fang et al. / International Journal of Cardiology 176 (2014) 80–85
particularly relevant to understanding the theoretical mechanisms of myocardial scintigraphic perfusion defects and the deterioration of left ventricular (LV) function after long-term RV pacing. Therefore, the aim of this prospective study was to explore the effect of RV pacing on coronary blood flow in left anterior descending artery (LAD) using noninvasive transthoracic echocardiography. In addition, the impact and relationship with systolic dyssynchrony were investigated in the current study. 2. Methods 2.1. Study population and study design From April 2005 through July 2009, a total of 70 patients with sick sinus dysfunction were prospectively enrolled in the study. All patients were examined before pacemaker implantation and followed up. The mean follow-up period was 127 ± 45 days. They all had normal cardiac function with ejection fraction ≥50% at baseline. Patients were excluded if they had coronary artery disease, a history of coronary artery bypass surgery, atrial fibrillation, patients with life expectancy b6 months,and pregnant. Patients were also excluded for those with suboptimal acoustic window who cannot be detected with LAD Doppler. ECG data and New York Heart Association class were also recorded. All the pacemaker parameters were retrieved from the internal monitor record. The study was approved and conducted in compliance with the regulation of the institutional Ethics Committee. 2.2. Transthoracic echocardiography Comprehensive transthoracic echocardiography (Vivid 7, General Electric) with tissue Doppler imaging (TDI) was performed to assess cardiac function and systolic dyssynchrony. Digital color TDI imaging was acquired with at least 3 cardiac consecutive beats on apical serial views (apical 4-chamber, 2-chamber, and long-axis views) after optimization of pulse repetition frequency, color saturation, sector size, and depth allowing the highest possible frame rate. Off-line analysis was performed with a dedicated software package (EchoPac 6.3.6, Vingmed, General Electric). Systolic dyssynchrony was calculated as the standard deviation of the time to peak myocardial systolic velocity in the ejection phase among the 12 left ventricular segments (Ts-SD) by using the QRS complex as the reference point. Systolic dyssynchrony was defined as Ts-SD ≥33 ms as reported previously. Tricuspid regurgitation was assessed by 2-dimensional color-flow and continuouswave Doppler [10]. RV long-axis function was evaluated using tricuspid annular plane systolic excursion (TAPSE), which was acquired by placing the M-mode cursor at the tricuspid annulus of the RV free wall from the apical 4-chamber view. Doppler study of distal LAD was done by placing the transducer in the 4th to 5th intercostal spaces on the modified apical 2-chamber view under the coronary examination item which can detect flow with low velocity. Under this specific blood flow guidance, the probe was adjusted to get the optimized long-axis flow view of the distal LAD after the detection long-axis color signal of LAD. The images were then zoomed and pulsed
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Doppler with sample volume (5 × 2.5 mm) on the distal portion of coronary artery was adopted to obtain the velocity. If there was Doppler angle between ultrasound beam and color signal, an angle correction was performed without exceeding 30°. Peak diastolic velocity, diastolic duration and velocity-time integral (VTI) were calculated [11–13]. 2.3. Statistical analysis Data were analyzed with the statistical software of SPSS version 17 (SPSS Inc, Chicago, Illinois, USA). All continuous variables were expressed as mean ± SD and Kolmogorov– Smirnov test was applied to test the normality. Paired t-test and independent t-test were used to compare the mean value of the parametric values as appropriate. Categorical variables were expressed as frequency and compared by Pearson Chi-square test or Fisher Exact test as appropriate. Pearson’s correlation was performed to test the correlations between parameters. Cox regression analysis was used to identify the predictors of the reduction of LAD VTI. Receiver Operating Characteristic (ROC) curve was performed to determine the cut‐off value of the potential parameter predicting LAD reduction. A significant difference was defined as p b 0.05 (2-tailed).
3. Results 3.1. Patients' characteristics Although 70 patients were enrolled 5 patients were excluded due to suboptimal LAD Doppler recording during on-line scanning. Therefore, the results from 65 patients were analyzed. The mean age was 57 ± 7 years and there were 45 (69%) males. Diabetes mellitus was found in 11 (17%) patients and hypertension in 26 (40%). The medical therapy included angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) in 15 (23%), calcium channel antagonists in 12 (19%) and statin in 16 (25%) as well as aspirin in 8 (12%) patients. 3.2. Clinical and echocardiographic changes before and after right ventricular apical pacing After pacing, QRS width was prolonged (100 ± 29 versus 129 ± 31 ms, p b 0.001) but New York Heart Association class remained unchanged (0.03 ± 0.17 versus 0.08 ± 0.17, p = 0.83). The changes of echocardiographic parameters after RV pacing are presented in Table 1. At follow-up, LV systolic function was reduced with an increase in LV end-systolic volume. Moreover, LV diastolic function was also decreased as evident by reduction of septal E′ and increase of E/E′ (both p b 0.05). Regarding LAD Doppler variables, peak velocity, VTI and diastolic duration were significantly reduced after pacing (all p b 0.01).
Table 1 Comparison of echocardiographic parameters between baseline and follow-up. Baseline
During follow-up
p Value
Cardiac function LVEDV, ml LVESV, ml LVEF, % Mitral E/A ratio LV septal E′ LV septal E/E′ TAPSE, cm Tricuspid regurgitation pressure gradient, mm Hg
57 ± 16 20 ± 7 65 ± 7 0.91 ± 0.33 7.4 ± 2.6 10.3 ± 3.9 2.0 ± 0.4 36 ± 9
62 ± 15 24 ± 8 62 ± 7 0.95 ± 0.36 7.1 ± 3.0 11.7 ± 5.2 1.7 ± 0.3 41 ± 13
0.024 0.001 0.014 0.203 0.027 0.002 b0.001 0.011
LAD Doppler Variables Peak diastolic velocities, cm/s LAD diastolic duration, ms LAD-VTI, cm
0.33 ± 0.12 520 ± 97 12.1 ± 4.2
0.26 ± 0.14 508 ± 95 10.7 ± 4.6
b0.001 0.007 b0.001
TDI variables Ts-SD, ms With systolic dyssynchrony, n (%) Te-SD, ms With diastolic dyssynchrony, n (%) Mean systolic septal velocity, cm/s Mean early diastolic septal velocity, cm/s
23 ± 7 4 (6) 27 ± 13 17 (26%) 3.9 ± 0.8 3.5 ± 1.1
39 ± 16 38 (59) 31 ± 15 22 (34%) 3.5 ± 0.8 2.9 ± 0.9
b0.001 χ2 = 40.03, p b 0.001 0.097 χ2 = 0.916, p = 0.222 b0.001 0.003
E′ = peak myocardial early diastolic velocity of mitral annulus by pulse wave tissue Doppler imaging; LAD = left anterior descending artery; LV = left ventricular; LVEDV = left ventricular diastolic volume; LVEF = left ventricular ejection fraction; LVESV = left ventricular end-systolic volume; TAPSE = tricuspid annular plane systolic excursion; VTI = velocity time integral; Te-SD = standard deviation of the time to early peak myocardial diastolic velocity among the 12 LV segments; Ts-SD = standard deviation of the time to systolic myocardial diastolic velocity among the 12 LV segments.
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Table 2 Comparison of baseline clinical and echocardiographic parameters in patients with and without pacing-induced systolic dyssynchrony. Without systolic dyssynchrony (n = 31)
With systolic dyssynchrony (n = 34)
p Value
Demographic parameters Sex, male/female (%)
20/11 (64.5)
25/9 (74%)
Age, year Systolic blood pressure, mm Hg Diastolic blood pressure, mm Hg Accumulative ventricular pacing percentage Pacing period, days ECG QRS duration, ms
57 ± 6 111 ± 10 70 ± 8 30 ± 15 113 ± 40 97 ± 27
56 ± 8 115 ± 7 71 ± 7 56 ± 23 140 ± 45 102 ± 31
χ2 = 0.618 p = 0.302 0.828 0.071 0.343 b0.001 0.014 0.506
Medical History, n (%) Hypertension
14 (45.2)
12 (35.3)
Diabetes mellitus
4 (12.9)
7 (20.6)
Medication, n (%) Calcium channel antagonist
4 (12.9)
8 (23.5)
Statin
10 (32.3)
6 (17.6)
Aspirin
3 (9.7)
5 (14.7)
ACEI/ARB
5 (16.1)
10 (29.4)
χ2 = 0.658 p = 0.289 χ2 = 0.681 p = 0.312 χ2 = 1.216 p = 0.218 χ2 = 1.866 p = 0.141 χ2 = 0.380 p = 0.408 χ2 = 1.612 p = 0.165
ACEI = angiotensin converting enzyme inhibitors; ARB = angiotensin receptor blockers.
By TDI, mean septal systolic and diastolic velocities were reduced significantly and systolic dyssynchrony was increased though the prevalence of systolic dyssynchrony was only 6% at baseline; however, diastolic dyssynchrony remained unchanged with similar prevalence before and after pacing (Table 1). Tricuspid regurgitation pressure gradient was slightly increased and TAPSE was reduced significantly (Table 1). 3.3. Comparison of clinical and echocardiographic parameters between patients with and without systolic dyssynchrony at follow-up At follow-up, using the validated cutoff value of Ts-SD ≥ 33 ms to define systolic dyssynchrony, more than half of patients (n = 34, 52%) had developed systolic dyssynchrony. As a group, these patients had higher pacing percentage and longer pacing period (Table 2) while other baseline characteristics were similar including age, gender, comorbidities and medication.
With respect to conventional and pulse tissue Doppler echocardiograhic parameters, both systolic and diastolic functions deteriorated in those with systolic dyssynchrony as evidenced by LV ejection fraction and LV septal E′ but remained unchanged in those without RV pacing induced systolic dyssynchrony (Table 3). Further measurement with color-coded TDI showed that deterioration of both mean septal systolic and diastolic velocities occurred only in those with RV pacing induced systolic dyssynchrony while there was no decline in patients without. Similarly, there was a significant reduction of LAD-VTI and peak velocity as well as LAD duration in the dyssynchrony group. In contrast, there was no intragroup difference in patients without dyssynchrony. Although LV volumes, LVEF, septal velocities and LAD variables were not different between the two groups at baseline, inter-group analysis showed that these parameters had significantly deterioration at follow-up in patients with dyssynchrony (Table 3).
Table 3 Comparison of changes in clinical and echocardiographic parameters at baseline and follow-up between 2 groups. Parameters
Without systolic dyssynchrony (n = 31)
With systolic dyssynchrony (n = 34)
Baseline
Follow-up
p Value
Baseline
Follow-up
p Value
Conventional echocardiographic variables LVEDV, ml LVESV, ml LVEF, % Mitral E/A ratio LV septal E′ Septal mitral E/E′
55 19 66 0.91 7.9 10.6
59 21 64 0.94 7.6 11.3
16 7 7 0.32 3.1 5.6
0.162 0.080 0.258 0.153 0.279 0.070
59 22 64 0.91 7.7 10
64 26 60 0.95 7.1 11
0.078 0.007 0.042 0.432 b0.001 0.001
LAD Doppler Variables Peak diastolic velocities, cm/s LAD-VTI, cm LAD diastolic duration, ms
36.4 ± 14.0 12.9 ± 4.8 530 ± 100
35.0 ± 15.0 13.0 ± 5.0 520 ± 95
0.254 0.640 0.650
38.0 ± 9.0 11.6 ± 3.2 518 ± 82
TDI variables Ts-SD, ms Te-SD, ms Mean systolic septal velocity, cm/s Mean diastolic septal velocity, cm/s
23 29 4.1 3.3
± ± ± ± ± ±
± ± ± ±
15 7 6 0.30 2.8 6.9
8 11 0.8 1.0
25 30 3.9 2.8
± ± ± ± ± ±
± ± ± ±
6 16 0.8 0.8
Abbreviation as in Tables 1 and 2. ⁎ p b 0.05 compared to the corresponding columns in patients without systolic dyssynchrony. ⁎⁎ p b 0.001 compared to the corresponding columns in patients without systolic dyssynchrony.
0.442 0.010 0.108 0.06
23 30 3.8 3.8
± ± ± ± ± ±
± ± ± ±
16 8 8 0.35 2.9 4
5 10 0.8 1.2
± ± ± ± ± ±
14 7⁎ 7⁎ 0.40 3.0 5
19.1 ± 12.0⁎ 8.7 ± 3.3⁎⁎ 454 ± 80⁎⁎
b0.001 b0.001 b0.001
11⁎⁎ 15⁎⁎ 0.8⁎⁎ 0.9
b0.001 0.514 b0.001 0.02
51 31 3.1 3.0
± ± ± ±
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3.4. Predictors of coronary blood flow reduction Significant coronary blood flow reduction was defined as LAD-VTI ≥5% after pacing and it was found in 34 (52.3%) patients after RV pacing, which was more prevalent in those with pacing induced systolic dyssynchrony (29, 85%) group than those without (5, 16.1%) (χ2 = 31.095, p b 0.001). Intriguingly, at follow-up there was an inverse correlation between Ts-SD and septal mean systolic velocity (r = − 0.468, p b 0.001) and LAD-VTI (r = − 0.384, p = 0.002) whereas a positive correlation was observed between septal velocity and LAD-VTI (r = 0.443, p b 0.001) (Fig. 1). However, there was no correlation between septal early diastolic velocity, LAD-VTI and early diastolic dyssynchrony (all p N 0.05). The univariate predictors for LAD-VTI reduction included older age, a higher accumulative pacing percentage and presence of systolic dyssynchrony at follow-up (Table 4). Further multivariate analysis showed that systolic dyssynchrony at follow-up [hazard ratio (HR): 3.114, 95% confidence interval: 1.004–9.655, p = 0.04] and a higher accumulative pacing percentage (HR: 1.014, 95% confidence interval: 1.000–1.029, p = 0.04) were independent predictors of reduction in LAD-VTI. Receiving operator curve showed that a cutoff value of accumulative pacing percentage ≥ 35% was 97% sensitive and 84% specific in predicting significant LAD-VTI reduction with the area under the curve (AUC) 0.96 (p b 0.001) (Fig. 2). 3.5. The inter- and intra-observer variability The inter- and intra-observer variability for LAD-VTI was 4.0% and 4.1% and 4.7% as well as 3.2% for Ts-SD, respectively, as previously reported. 4. Discussion The present study prospectively enrolled relatively large number of patients with RV pacemaker implantation without pre-existing coronary artery disease. The main findings were that coronary blood flow in the distal LAD was reduced after mid-term of RV pacing, which was mainly observed in those with RV pacing induced systolic dyssynchrony. Also, it was found that LAD flow reduction was independently predicted by RV-included systolic dyssynchrony and a higher cumulative amount of ventricular pacing during the follow-up period. 4.1. Myocardial perfusion, coronary blood flow and RV pacing Septal perfusion defects have been detected in patients with isolated LBBB in septal and anterior walls even in those without pre-existing coronary artery disease at both rest and during exercise [6,14]. A study with 10 patients using PET demonstrated that LBBB resulted in septal perfusion defect due to hyperperfusion in lateral wall and therefore the ratio of septal/lateral myocardial perfusion decreased especially during exercise [14]. However, published data remains inconclusive on the impact of RV pacing on coronary blood flow. With intracoronary Doppler, it was shown that LAD velocity was increased which might be due to increased myocardial oxygen demand [15]. Whereas in a study with transthoracic echocardiography, both peak velocity and velocitytime integral were significantly less in patients having LBBB and systolic dysfunction than normal controls [6]. Although iatrogenic LBBB is present in RV pacing, whether RV pacing-induced LBBB produces a similar effect in those with normal LV ejection fraction remains to be addressed. In the current study, LAD Doppler was observed to be significantly reduced after RV pacing. This is in contrast to a previous cross-sectional study that reported that LAD Doppler was similar in RV pacing patients when compared to normal controls [6]. This discrepancy might be related to the time-effect of RV pacing. Duration of pacing is also likely to be an important factor on the impact of RV pacing. Further studies are needed to establish whether over the long term coronary blood flow will deteriorate more. If the harmful effects of RV pacing on LAD flow take time to
Fig. 1. Scatter plots showing the correlation between septal mean myocardium systolic velocity and velocity-time integral of left anterior descending coronary artery (LAD-VTI) The symbol “▲” denotes patients without pacing-induced systolic dyssynchrony and the "□" denotes patients with systolic dyssynchrony. (1a). Correlation between septal mean myocardium systolic velocity and systolic dyssycnhrony (1b) as well as the correlation between LAD-VTI and systolic dyssynchrony (1c).
develop symptoms then echocardiographic investigation with LAD Doppler may help in monitoring the potential risk before myocardial depression and symptoms develop.
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Table 4 Univariate and multivariate cox regression analyses to examine for significant determinant(s) of the reduction of flow of left anterior descending artery during follow-up. Parameter
Age, years Sex, M/F Baseline ECG QRS width, ms Cumulative ventricular pacing percentage With pacing induced systolic dyssynchrony
Univariate model
Multivariate model
Hazard ratio (95% confidence interval)
p Value
Hazard ratio (95% confidence interval)
p Value
1.043 (0.997–1.072) 0.714(0.353–1.445) 1.001 (0.984–1.018) 1.019(1.006–1.033) 3.618 (1.388–9.430)
0.034 0.350 0.938 0.005 0.009
– – – 1.014 (1.000–1.029) 3.114 (1.004–9.655)
– – – 0.04 0.04
Abbreviations as in Table 1.
4.2. Determinants of coronary blood flow during RV pacing Not every patient with RV pacing has coronary blood flow impairment. Consequently, it is worthwhile to seek the possible factors associated with LAD flow reduction. In this study, we identified pacinginduced systolic dyssynchrony and a higher cumulative amount of ventricular pacing were predictors for the unfavorable effects on coronary blood flow. Both systolic and diastolic functions can be affected by systolic dyssynchrony during acute or long-term RV pacing as shown by TDI and speckle tracking imaging [16–19]. Our data also showed that systolic septal velocity was decreased in those with systolic dyssynchrony and that systolic velocity was correlated to both dyssynchrony index and LAD flow parameters. This could be explained as less septal contribution to overall LV contraction due to the dyssynchronous pattern of activation and therefore oxygen demand in septal region is reduced. Moreover, RV pacing over time can lead to the alteration of myocardial architecture and myofibrillar disarray after long-term dyssynchronous contraction and subsequently regional myocardial strain as well as working load are reduced [20], which will result in a reduction of coronary blood flow due to redistribution. Another interesting finding was that higher cumulative percentage of RV pacing percentage was related to coronary blood flow reduction
beyond the development of systolic dyssynchrony. In patients with reduced ejection fraction, the risk of mortality and heart failure was greater when ventricular pacing percentage was N 40% [21]. It was also found that the longer the patients were exposed to RV pacing the higher likelihood that electromechanical delay will develop leading to impairment of LV systolic function. 4.3. Clinical implication RV pacing impairs systolic and diastolic functions and coronary blood flow especially in those with pacing-induced systolic dyssynchrony. Therefore, attempts to minimize ventricular pacing would be the best strategy. Moreover, alternative pacing sites other than RV should be considered when ventricular pacing is necessary. The use of biventricular pacing has been demonstrated to prevent LV remodeling in those with early systolic dyssynchrony induced by RV pacing [19]. Therefore, it seems sensible to determine beforehand whether the patient is likely to be susceptible to the adverse effects of RV pacing. The use of echocardiographic techniques to screen for the early occurrence of dyssynchrony at the time of implantation may play a role in selecting the correct pacing modality. The ongoing ENHANCE trial is aimed to determine whether cardiac resynchronization therapy can prevent cardiac remodeling in those who have RV pacing induced systolic dyssynchrony. 4.4. Study limitations The current study had several limitations. Firstly, we detected LAD blood flow without the examination of left circumflex coronary artery or right coronary artery. And the cut-off point of LAD reduction with 5% was an arbitrary value. Secondly, we did not assess coronary blood reserve and it would be interesting to explore the LAD blood flow during stress or exercise. Thirdly, the follow-up time was relatively short although previous studies have consistently reported that LAD flow changes occurred after 3 months. Moreover, not every patient had a coronary angiogram examination and the definition of those without pre-existing coronary artery disease was based on medical history, ECG and biochemical indicators. And BNP measurement was not available for this study. Finally, an acute study assessing the effect of pacemaker on/off on the coronary blood-flow immediately may better elucidate the impact of RV pacing on myocardial perfusion. 5. Conclusion
Fig. 2. ROC curve predicting significant reduction of velocity-time integral of left anterior descending coronary artery as reflected by accumulative ventricular pacing percentage dispersion [solid line, AUC = 0.96, p b 0.001].
We conclude that RV pacing may induce LAD blood flow reduction at rest, in particular in patients with RV pacing-induced systolic dyssynchrony and higher accumulative percentage of pacing. Quantification of LAD Doppler with transthoracic echocardiography enables the monitoring of coronary blood flow. Our findings provide another insight in the mechanisms of the unfavorable effect of RV pacing and indicate that in the early detection of potential adverse effects on myocardial function and coronary blood flow may be possible using these techniques prior to permanent implantation. Whether the reduction of LAD blood flow is directly related to patients' symptoms warrants a further study.
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Conflict of interest There is no conflict of interest.
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Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Left anterior descending coronary artery flow impaired by right ventricular apical pacing: The role of systolic dyssynchrony Fang Fang a,b,1, Ze-Ning Jin b,1, Hai-Yan Li b,1, Wei-Jun Zhang b, Zhi-An Li b, Ya Yang b, Xiu-Xia Luo a, Zhi-Hua Zhang a, Alex Pui-Wai Lee a, Cheuk-Man Yu a,⁎, John E. Sanderson a a
Division of Cardiology, Department of Medicine and Therapeutics, Institute of Vascular Medicine; Institute of Innovative Medicine; HEART Center; and Li Ka Shing Institute of Health Sciences, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong Beijing AnZhen Hospital, Capital Medical University, China
b
a r t i c l e
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Article history: Received 18 February 2014 Received in revised form 26 May 2014 Accepted 24 June 2014 Available online 2 July 2014 Keywords: Left anterior descending artery Right ventricular apical pacing systolic dyssynchrony
a b s t r a c t Introduction: Right ventricular (RV) pacing may affect myocardial perfusion and coronary blood flow; however, it remains unknown whether this is related to systolic dyssynchrony induced by RV pacing. This prospective study was aimed to assess the relationship between dyssynchrony and the changes of coronary blood flow. Methods: Seventy patients with sinus node dysfunction were prospectively enrolled. Coronary flow was evaluated by measuring diastolic velocity time integral (VTI) and duration at the distal-portion of left anterior descending coronary artery (LAD) with transthoracic echocardiography at baseline and follow-up. Systolic dyssynchrony was assessed with tissue Doppler imaging by time standard deviation to peak systolic velocity of 12 left ventricular segments (Ts-SD, cutoff value ≥33 ms). Results: Adequate data for analysis was available from 65 patients. At follow-up (mean follow up time: 127 ± 45 days), LAD velocity-time integral (LAD-VTI: 12.1 ± 4.2 vs. 10.7 ± 4.6 cm, p b 0.001) was decreased and there was deterioration of left ventricular systolic function (left ventricular ejection fraction: 65 ± 7% vs. 62 ± 7%). However, these changes were only detected in those with RV pacing induced systolic dyssynchrony. Significant reduction of LAD-VTI (defined as ≥5%) occurred in 34 (52%) patients which was more prevalent in those with pacing-induced systolic dyssynchrony than those without (85.3% versus 16.1%, χ2 = 31.1, p b 0.001). Though similar at baseline, LAD-VTI was significantly lower in the dyssynchrony group at follow up (p b 0.001). Cox-regression analysis showed that pacing-inducing systolic dyssynchrony [hazard ratio (HR): 3.62, p = 0.009] and higher accumulative pacing percentage (HR: 1.02, p = 0.002) were independently associated with reduction of LAD-VTI. ROC curve demonstrated that accumulative pacing percentage ≥35% was 97% sensitive and 84% specific in revealing significant reduction (area under the curve: 0.961, p b 0.001). Conclusions: RV pacing induced dyssynchrony is associated with reduced coronary flow and this may account for, in part, the deleterious effect of RV pacing on ventricular function over time. © 2014 Published by Elsevier Ireland Ltd.
1. Introduction
Abbreviations: E′, peak myocardial early diastolic velocity of mitral annulus by pulse wave tissue Doppler imaging; LAD, left anterior descending coronary artery; LV, left ventricle/left ventricular; LVEDV, left ventricular end-diastolic volume; LVEF, left ventricular ejection fraction; LVESV, left ventricular end-systolic volume; RV, right ventricular; TAPSE, tricuspid annular plane systolic excursion; TDI, tissue Doppler imaging; Te-SD, standard deviation of the time to early peak myocardial diastolic velocity among the 12 LV segments; Ts-SD, standard deviation of the time to peak myocardial systolic velocity among the 12 LV segments; VTI, velocity-time integral. ⁎ Corresponding author at: Division of Cardiology, Department of Medicine and Therapeutics, Institute of Vascular Medicine, Institute of Innovative Medicine, HEART Center, and Li Ka Shing Institute of Health Sciences, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong. Tel.: +852 2632 3594; fax: +852 2637 5643. E-mail address: [email protected] (C.-M. Yu). 1 All the authors were equally contributed.
http://dx.doi.org/10.1016/j.ijcard.2014.06.037 0167-5273/© 2014 Published by Elsevier Ireland Ltd.
It has become apparent that not only systolic function but also diastolic function could be impaired after long-term pacing even in patients with normal cardiac function, and this has been considered to be related to systolic dyssynchrony induced by the non-physiological conduction during right ventricular apical (RV) pacing [1,2]. Recent studies have shown that RV pacing can lead to regional perfusion defects, reduction of myocardial oxygen consumption as well as cardiac efficiency even in those without pre-existing coronary artery disease [3–5]. Coronary blood flow detected with transthoracic echocardiography that been shown to be disturbed in patients with LBBB; [6] whereas, data are inconclusive with regard to the coronary flow change after RV pacing despite the presence of an iatrogenic LBBB [6–9]. Furthermore, whether the impact of RV pacing on coronary blood flow is related to pacing-induced systolic dyssynchrony has not been elucidated. This is
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particularly relevant to understanding the theoretical mechanisms of myocardial scintigraphic perfusion defects and the deterioration of left ventricular (LV) function after long-term RV pacing. Therefore, the aim of this prospective study was to explore the effect of RV pacing on coronary blood flow in left anterior descending artery (LAD) using noninvasive transthoracic echocardiography. In addition, the impact and relationship with systolic dyssynchrony were investigated in the current study. 2. Methods 2.1. Study population and study design From April 2005 through July 2009, a total of 70 patients with sick sinus dysfunction were prospectively enrolled in the study. All patients were examined before pacemaker implantation and followed up. The mean follow-up period was 127 ± 45 days. They all had normal cardiac function with ejection fraction ≥50% at baseline. Patients were excluded if they had coronary artery disease, a history of coronary artery bypass surgery, atrial fibrillation, patients with life expectancy b6 months,and pregnant. Patients were also excluded for those with suboptimal acoustic window who cannot be detected with LAD Doppler. ECG data and New York Heart Association class were also recorded. All the pacemaker parameters were retrieved from the internal monitor record. The study was approved and conducted in compliance with the regulation of the institutional Ethics Committee. 2.2. Transthoracic echocardiography Comprehensive transthoracic echocardiography (Vivid 7, General Electric) with tissue Doppler imaging (TDI) was performed to assess cardiac function and systolic dyssynchrony. Digital color TDI imaging was acquired with at least 3 cardiac consecutive beats on apical serial views (apical 4-chamber, 2-chamber, and long-axis views) after optimization of pulse repetition frequency, color saturation, sector size, and depth allowing the highest possible frame rate. Off-line analysis was performed with a dedicated software package (EchoPac 6.3.6, Vingmed, General Electric). Systolic dyssynchrony was calculated as the standard deviation of the time to peak myocardial systolic velocity in the ejection phase among the 12 left ventricular segments (Ts-SD) by using the QRS complex as the reference point. Systolic dyssynchrony was defined as Ts-SD ≥33 ms as reported previously. Tricuspid regurgitation was assessed by 2-dimensional color-flow and continuouswave Doppler [10]. RV long-axis function was evaluated using tricuspid annular plane systolic excursion (TAPSE), which was acquired by placing the M-mode cursor at the tricuspid annulus of the RV free wall from the apical 4-chamber view. Doppler study of distal LAD was done by placing the transducer in the 4th to 5th intercostal spaces on the modified apical 2-chamber view under the coronary examination item which can detect flow with low velocity. Under this specific blood flow guidance, the probe was adjusted to get the optimized long-axis flow view of the distal LAD after the detection long-axis color signal of LAD. The images were then zoomed and pulsed
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Doppler with sample volume (5 × 2.5 mm) on the distal portion of coronary artery was adopted to obtain the velocity. If there was Doppler angle between ultrasound beam and color signal, an angle correction was performed without exceeding 30°. Peak diastolic velocity, diastolic duration and velocity-time integral (VTI) were calculated [11–13]. 2.3. Statistical analysis Data were analyzed with the statistical software of SPSS version 17 (SPSS Inc, Chicago, Illinois, USA). All continuous variables were expressed as mean ± SD and Kolmogorov– Smirnov test was applied to test the normality. Paired t-test and independent t-test were used to compare the mean value of the parametric values as appropriate. Categorical variables were expressed as frequency and compared by Pearson Chi-square test or Fisher Exact test as appropriate. Pearson’s correlation was performed to test the correlations between parameters. Cox regression analysis was used to identify the predictors of the reduction of LAD VTI. Receiver Operating Characteristic (ROC) curve was performed to determine the cut‐off value of the potential parameter predicting LAD reduction. A significant difference was defined as p b 0.05 (2-tailed).
3. Results 3.1. Patients' characteristics Although 70 patients were enrolled 5 patients were excluded due to suboptimal LAD Doppler recording during on-line scanning. Therefore, the results from 65 patients were analyzed. The mean age was 57 ± 7 years and there were 45 (69%) males. Diabetes mellitus was found in 11 (17%) patients and hypertension in 26 (40%). The medical therapy included angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) in 15 (23%), calcium channel antagonists in 12 (19%) and statin in 16 (25%) as well as aspirin in 8 (12%) patients. 3.2. Clinical and echocardiographic changes before and after right ventricular apical pacing After pacing, QRS width was prolonged (100 ± 29 versus 129 ± 31 ms, p b 0.001) but New York Heart Association class remained unchanged (0.03 ± 0.17 versus 0.08 ± 0.17, p = 0.83). The changes of echocardiographic parameters after RV pacing are presented in Table 1. At follow-up, LV systolic function was reduced with an increase in LV end-systolic volume. Moreover, LV diastolic function was also decreased as evident by reduction of septal E′ and increase of E/E′ (both p b 0.05). Regarding LAD Doppler variables, peak velocity, VTI and diastolic duration were significantly reduced after pacing (all p b 0.01).
Table 1 Comparison of echocardiographic parameters between baseline and follow-up. Baseline
During follow-up
p Value
Cardiac function LVEDV, ml LVESV, ml LVEF, % Mitral E/A ratio LV septal E′ LV septal E/E′ TAPSE, cm Tricuspid regurgitation pressure gradient, mm Hg
57 ± 16 20 ± 7 65 ± 7 0.91 ± 0.33 7.4 ± 2.6 10.3 ± 3.9 2.0 ± 0.4 36 ± 9
62 ± 15 24 ± 8 62 ± 7 0.95 ± 0.36 7.1 ± 3.0 11.7 ± 5.2 1.7 ± 0.3 41 ± 13
0.024 0.001 0.014 0.203 0.027 0.002 b0.001 0.011
LAD Doppler Variables Peak diastolic velocities, cm/s LAD diastolic duration, ms LAD-VTI, cm
0.33 ± 0.12 520 ± 97 12.1 ± 4.2
0.26 ± 0.14 508 ± 95 10.7 ± 4.6
b0.001 0.007 b0.001
TDI variables Ts-SD, ms With systolic dyssynchrony, n (%) Te-SD, ms With diastolic dyssynchrony, n (%) Mean systolic septal velocity, cm/s Mean early diastolic septal velocity, cm/s
23 ± 7 4 (6) 27 ± 13 17 (26%) 3.9 ± 0.8 3.5 ± 1.1
39 ± 16 38 (59) 31 ± 15 22 (34%) 3.5 ± 0.8 2.9 ± 0.9
b0.001 χ2 = 40.03, p b 0.001 0.097 χ2 = 0.916, p = 0.222 b0.001 0.003
E′ = peak myocardial early diastolic velocity of mitral annulus by pulse wave tissue Doppler imaging; LAD = left anterior descending artery; LV = left ventricular; LVEDV = left ventricular diastolic volume; LVEF = left ventricular ejection fraction; LVESV = left ventricular end-systolic volume; TAPSE = tricuspid annular plane systolic excursion; VTI = velocity time integral; Te-SD = standard deviation of the time to early peak myocardial diastolic velocity among the 12 LV segments; Ts-SD = standard deviation of the time to systolic myocardial diastolic velocity among the 12 LV segments.
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Table 2 Comparison of baseline clinical and echocardiographic parameters in patients with and without pacing-induced systolic dyssynchrony. Without systolic dyssynchrony (n = 31)
With systolic dyssynchrony (n = 34)
p Value
Demographic parameters Sex, male/female (%)
20/11 (64.5)
25/9 (74%)
Age, year Systolic blood pressure, mm Hg Diastolic blood pressure, mm Hg Accumulative ventricular pacing percentage Pacing period, days ECG QRS duration, ms
57 ± 6 111 ± 10 70 ± 8 30 ± 15 113 ± 40 97 ± 27
56 ± 8 115 ± 7 71 ± 7 56 ± 23 140 ± 45 102 ± 31
χ2 = 0.618 p = 0.302 0.828 0.071 0.343 b0.001 0.014 0.506
Medical History, n (%) Hypertension
14 (45.2)
12 (35.3)
Diabetes mellitus
4 (12.9)
7 (20.6)
Medication, n (%) Calcium channel antagonist
4 (12.9)
8 (23.5)
Statin
10 (32.3)
6 (17.6)
Aspirin
3 (9.7)
5 (14.7)
ACEI/ARB
5 (16.1)
10 (29.4)
χ2 = 0.658 p = 0.289 χ2 = 0.681 p = 0.312 χ2 = 1.216 p = 0.218 χ2 = 1.866 p = 0.141 χ2 = 0.380 p = 0.408 χ2 = 1.612 p = 0.165
ACEI = angiotensin converting enzyme inhibitors; ARB = angiotensin receptor blockers.
By TDI, mean septal systolic and diastolic velocities were reduced significantly and systolic dyssynchrony was increased though the prevalence of systolic dyssynchrony was only 6% at baseline; however, diastolic dyssynchrony remained unchanged with similar prevalence before and after pacing (Table 1). Tricuspid regurgitation pressure gradient was slightly increased and TAPSE was reduced significantly (Table 1). 3.3. Comparison of clinical and echocardiographic parameters between patients with and without systolic dyssynchrony at follow-up At follow-up, using the validated cutoff value of Ts-SD ≥ 33 ms to define systolic dyssynchrony, more than half of patients (n = 34, 52%) had developed systolic dyssynchrony. As a group, these patients had higher pacing percentage and longer pacing period (Table 2) while other baseline characteristics were similar including age, gender, comorbidities and medication.
With respect to conventional and pulse tissue Doppler echocardiograhic parameters, both systolic and diastolic functions deteriorated in those with systolic dyssynchrony as evidenced by LV ejection fraction and LV septal E′ but remained unchanged in those without RV pacing induced systolic dyssynchrony (Table 3). Further measurement with color-coded TDI showed that deterioration of both mean septal systolic and diastolic velocities occurred only in those with RV pacing induced systolic dyssynchrony while there was no decline in patients without. Similarly, there was a significant reduction of LAD-VTI and peak velocity as well as LAD duration in the dyssynchrony group. In contrast, there was no intragroup difference in patients without dyssynchrony. Although LV volumes, LVEF, septal velocities and LAD variables were not different between the two groups at baseline, inter-group analysis showed that these parameters had significantly deterioration at follow-up in patients with dyssynchrony (Table 3).
Table 3 Comparison of changes in clinical and echocardiographic parameters at baseline and follow-up between 2 groups. Parameters
Without systolic dyssynchrony (n = 31)
With systolic dyssynchrony (n = 34)
Baseline
Follow-up
p Value
Baseline
Follow-up
p Value
Conventional echocardiographic variables LVEDV, ml LVESV, ml LVEF, % Mitral E/A ratio LV septal E′ Septal mitral E/E′
55 19 66 0.91 7.9 10.6
59 21 64 0.94 7.6 11.3
16 7 7 0.32 3.1 5.6
0.162 0.080 0.258 0.153 0.279 0.070
59 22 64 0.91 7.7 10
64 26 60 0.95 7.1 11
0.078 0.007 0.042 0.432 b0.001 0.001
LAD Doppler Variables Peak diastolic velocities, cm/s LAD-VTI, cm LAD diastolic duration, ms
36.4 ± 14.0 12.9 ± 4.8 530 ± 100
35.0 ± 15.0 13.0 ± 5.0 520 ± 95
0.254 0.640 0.650
38.0 ± 9.0 11.6 ± 3.2 518 ± 82
TDI variables Ts-SD, ms Te-SD, ms Mean systolic septal velocity, cm/s Mean diastolic septal velocity, cm/s
23 29 4.1 3.3
± ± ± ± ± ±
± ± ± ±
15 7 6 0.30 2.8 6.9
8 11 0.8 1.0
25 30 3.9 2.8
± ± ± ± ± ±
± ± ± ±
6 16 0.8 0.8
Abbreviation as in Tables 1 and 2. ⁎ p b 0.05 compared to the corresponding columns in patients without systolic dyssynchrony. ⁎⁎ p b 0.001 compared to the corresponding columns in patients without systolic dyssynchrony.
0.442 0.010 0.108 0.06
23 30 3.8 3.8
± ± ± ± ± ±
± ± ± ±
16 8 8 0.35 2.9 4
5 10 0.8 1.2
± ± ± ± ± ±
14 7⁎ 7⁎ 0.40 3.0 5
19.1 ± 12.0⁎ 8.7 ± 3.3⁎⁎ 454 ± 80⁎⁎
b0.001 b0.001 b0.001
11⁎⁎ 15⁎⁎ 0.8⁎⁎ 0.9
b0.001 0.514 b0.001 0.02
51 31 3.1 3.0
± ± ± ±
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3.4. Predictors of coronary blood flow reduction Significant coronary blood flow reduction was defined as LAD-VTI ≥5% after pacing and it was found in 34 (52.3%) patients after RV pacing, which was more prevalent in those with pacing induced systolic dyssynchrony (29, 85%) group than those without (5, 16.1%) (χ2 = 31.095, p b 0.001). Intriguingly, at follow-up there was an inverse correlation between Ts-SD and septal mean systolic velocity (r = − 0.468, p b 0.001) and LAD-VTI (r = − 0.384, p = 0.002) whereas a positive correlation was observed between septal velocity and LAD-VTI (r = 0.443, p b 0.001) (Fig. 1). However, there was no correlation between septal early diastolic velocity, LAD-VTI and early diastolic dyssynchrony (all p N 0.05). The univariate predictors for LAD-VTI reduction included older age, a higher accumulative pacing percentage and presence of systolic dyssynchrony at follow-up (Table 4). Further multivariate analysis showed that systolic dyssynchrony at follow-up [hazard ratio (HR): 3.114, 95% confidence interval: 1.004–9.655, p = 0.04] and a higher accumulative pacing percentage (HR: 1.014, 95% confidence interval: 1.000–1.029, p = 0.04) were independent predictors of reduction in LAD-VTI. Receiving operator curve showed that a cutoff value of accumulative pacing percentage ≥ 35% was 97% sensitive and 84% specific in predicting significant LAD-VTI reduction with the area under the curve (AUC) 0.96 (p b 0.001) (Fig. 2). 3.5. The inter- and intra-observer variability The inter- and intra-observer variability for LAD-VTI was 4.0% and 4.1% and 4.7% as well as 3.2% for Ts-SD, respectively, as previously reported. 4. Discussion The present study prospectively enrolled relatively large number of patients with RV pacemaker implantation without pre-existing coronary artery disease. The main findings were that coronary blood flow in the distal LAD was reduced after mid-term of RV pacing, which was mainly observed in those with RV pacing induced systolic dyssynchrony. Also, it was found that LAD flow reduction was independently predicted by RV-included systolic dyssynchrony and a higher cumulative amount of ventricular pacing during the follow-up period. 4.1. Myocardial perfusion, coronary blood flow and RV pacing Septal perfusion defects have been detected in patients with isolated LBBB in septal and anterior walls even in those without pre-existing coronary artery disease at both rest and during exercise [6,14]. A study with 10 patients using PET demonstrated that LBBB resulted in septal perfusion defect due to hyperperfusion in lateral wall and therefore the ratio of septal/lateral myocardial perfusion decreased especially during exercise [14]. However, published data remains inconclusive on the impact of RV pacing on coronary blood flow. With intracoronary Doppler, it was shown that LAD velocity was increased which might be due to increased myocardial oxygen demand [15]. Whereas in a study with transthoracic echocardiography, both peak velocity and velocitytime integral were significantly less in patients having LBBB and systolic dysfunction than normal controls [6]. Although iatrogenic LBBB is present in RV pacing, whether RV pacing-induced LBBB produces a similar effect in those with normal LV ejection fraction remains to be addressed. In the current study, LAD Doppler was observed to be significantly reduced after RV pacing. This is in contrast to a previous cross-sectional study that reported that LAD Doppler was similar in RV pacing patients when compared to normal controls [6]. This discrepancy might be related to the time-effect of RV pacing. Duration of pacing is also likely to be an important factor on the impact of RV pacing. Further studies are needed to establish whether over the long term coronary blood flow will deteriorate more. If the harmful effects of RV pacing on LAD flow take time to
Fig. 1. Scatter plots showing the correlation between septal mean myocardium systolic velocity and velocity-time integral of left anterior descending coronary artery (LAD-VTI) The symbol “▲” denotes patients without pacing-induced systolic dyssynchrony and the "□" denotes patients with systolic dyssynchrony. (1a). Correlation between septal mean myocardium systolic velocity and systolic dyssycnhrony (1b) as well as the correlation between LAD-VTI and systolic dyssynchrony (1c).
develop symptoms then echocardiographic investigation with LAD Doppler may help in monitoring the potential risk before myocardial depression and symptoms develop.
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Table 4 Univariate and multivariate cox regression analyses to examine for significant determinant(s) of the reduction of flow of left anterior descending artery during follow-up. Parameter
Age, years Sex, M/F Baseline ECG QRS width, ms Cumulative ventricular pacing percentage With pacing induced systolic dyssynchrony
Univariate model
Multivariate model
Hazard ratio (95% confidence interval)
p Value
Hazard ratio (95% confidence interval)
p Value
1.043 (0.997–1.072) 0.714(0.353–1.445) 1.001 (0.984–1.018) 1.019(1.006–1.033) 3.618 (1.388–9.430)
0.034 0.350 0.938 0.005 0.009
– – – 1.014 (1.000–1.029) 3.114 (1.004–9.655)
– – – 0.04 0.04
Abbreviations as in Table 1.
4.2. Determinants of coronary blood flow during RV pacing Not every patient with RV pacing has coronary blood flow impairment. Consequently, it is worthwhile to seek the possible factors associated with LAD flow reduction. In this study, we identified pacinginduced systolic dyssynchrony and a higher cumulative amount of ventricular pacing were predictors for the unfavorable effects on coronary blood flow. Both systolic and diastolic functions can be affected by systolic dyssynchrony during acute or long-term RV pacing as shown by TDI and speckle tracking imaging [16–19]. Our data also showed that systolic septal velocity was decreased in those with systolic dyssynchrony and that systolic velocity was correlated to both dyssynchrony index and LAD flow parameters. This could be explained as less septal contribution to overall LV contraction due to the dyssynchronous pattern of activation and therefore oxygen demand in septal region is reduced. Moreover, RV pacing over time can lead to the alteration of myocardial architecture and myofibrillar disarray after long-term dyssynchronous contraction and subsequently regional myocardial strain as well as working load are reduced [20], which will result in a reduction of coronary blood flow due to redistribution. Another interesting finding was that higher cumulative percentage of RV pacing percentage was related to coronary blood flow reduction
beyond the development of systolic dyssynchrony. In patients with reduced ejection fraction, the risk of mortality and heart failure was greater when ventricular pacing percentage was N 40% [21]. It was also found that the longer the patients were exposed to RV pacing the higher likelihood that electromechanical delay will develop leading to impairment of LV systolic function. 4.3. Clinical implication RV pacing impairs systolic and diastolic functions and coronary blood flow especially in those with pacing-induced systolic dyssynchrony. Therefore, attempts to minimize ventricular pacing would be the best strategy. Moreover, alternative pacing sites other than RV should be considered when ventricular pacing is necessary. The use of biventricular pacing has been demonstrated to prevent LV remodeling in those with early systolic dyssynchrony induced by RV pacing [19]. Therefore, it seems sensible to determine beforehand whether the patient is likely to be susceptible to the adverse effects of RV pacing. The use of echocardiographic techniques to screen for the early occurrence of dyssynchrony at the time of implantation may play a role in selecting the correct pacing modality. The ongoing ENHANCE trial is aimed to determine whether cardiac resynchronization therapy can prevent cardiac remodeling in those who have RV pacing induced systolic dyssynchrony. 4.4. Study limitations The current study had several limitations. Firstly, we detected LAD blood flow without the examination of left circumflex coronary artery or right coronary artery. And the cut-off point of LAD reduction with 5% was an arbitrary value. Secondly, we did not assess coronary blood reserve and it would be interesting to explore the LAD blood flow during stress or exercise. Thirdly, the follow-up time was relatively short although previous studies have consistently reported that LAD flow changes occurred after 3 months. Moreover, not every patient had a coronary angiogram examination and the definition of those without pre-existing coronary artery disease was based on medical history, ECG and biochemical indicators. And BNP measurement was not available for this study. Finally, an acute study assessing the effect of pacemaker on/off on the coronary blood-flow immediately may better elucidate the impact of RV pacing on myocardial perfusion. 5. Conclusion
Fig. 2. ROC curve predicting significant reduction of velocity-time integral of left anterior descending coronary artery as reflected by accumulative ventricular pacing percentage dispersion [solid line, AUC = 0.96, p b 0.001].
We conclude that RV pacing may induce LAD blood flow reduction at rest, in particular in patients with RV pacing-induced systolic dyssynchrony and higher accumulative percentage of pacing. Quantification of LAD Doppler with transthoracic echocardiography enables the monitoring of coronary blood flow. Our findings provide another insight in the mechanisms of the unfavorable effect of RV pacing and indicate that in the early detection of potential adverse effects on myocardial function and coronary blood flow may be possible using these techniques prior to permanent implantation. Whether the reduction of LAD blood flow is directly related to patients' symptoms warrants a further study.
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Conflict of interest There is no conflict of interest.
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