Increased percentage of Atrial Pace Ventricular Pace was associated with increased cardiovascular morality in patients with a DDD pacemaker

Background Compared to single-chamber pacing system, dual chamber atrioventricular pacing system (DDD) was associated with reduced mortality and hospitalization for heart failure. High percentage of right ventricular pacing was reported to be associated with high cardiovascular events. However, another meta-analysis study showed ventricular pacing reduction modalities did not improve adverse clinical outcomes. Hence, the relationship between the pacing percentage and clinical outcomes is necessary to be further studied. The present study was designed to evaluate the association of total and cardiovascular mortality with the percentages of atrial sense ventricular sense (ASVS), atrial sense ventricular pace (ASVP), atrial pace ventricular sense (APVS), and atrial pace ventricular pace (APVP) in patients with a DDD pacemaker. Study subjects were selected from patients arranged for permanent pacemaker follow-up at our special clinic. 177 patients with a DDD pacemaker were included. We collected their pacemaker follow-up data at their rst visit for pacemaker follow-up after permanent pacemaker implantation.


Background
Compared to single-chamber pacing system, dual chamber atrioventricular pacing system (DDD) was associated with reduced mortality and hospitalization for heart failure. High percentage of right ventricular pacing was reported to be associated with high cardiovascular events. However, another metaanalysis study showed ventricular pacing reduction modalities did not improve adverse clinical outcomes. Hence, the relationship between the pacing percentage and clinical outcomes is necessary to be further studied.

Methods
The present study was designed to evaluate the association of total and cardiovascular mortality with the percentages of atrial sense ventricular sense (ASVS), atrial sense ventricular pace (ASVP), atrial pace ventricular sense (APVS), and atrial pace ventricular pace (APVP) in patients with a DDD pacemaker. Study subjects were selected from patients arranged for permanent pacemaker follow-up at our special clinic. 177 patients with a DDD pacemaker were included. We collected their pacemaker follow-up data at their rst visit for pacemaker follow-up after permanent pacemaker implantation.

Results
Among the 177 subjects, the mean follow-up to mortality was 2.44 ± 1.03 years. There were 22 and 10 patients documented as total and cardiovascular mortality. In the Cox proportional hazards regression analysis, old age (P = 0.030) and low hemoglobin (P = 0.007) were the predictors of increased total mortality and increased creatinine (P = 0.023) and high percentage of APVP (hazard ratio [HR], 1.030; 95% con dence interval [CI], 1.012-1.049; P = 0.001) were the predictors of increased cardiovascular mortality after multivariable analysis.

Conclusion
In patients with a DDD pacemaker, old age and low hemoglobin were associated with increased total mortality and high creatinene and high percentage of APVP were associated with increased cardiovascular mortality after multivariable analysis. Hence, reduction in unnecessary atrial and ventricular pacing in patients with a DDD pacemaker might be useful in improving cardiovascular prognosis.

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Cardiac pacing is the well-established treatment for patients with bradycardia. Pacemaker technology permits the use of either single-chamber ventricular pacemakers or dual-chamber pacemakers (DDD) for patients without permanent atrial brillation who require cardiac pacing. Compared to single-chamber pacing, dual-chamber pacing more closely resembles cardiac physiology by maintaining atrioventricular (AV) synchrony and thus reduces cardiovascular morbidity and mortality [1][2][3] and improves quality of life [4,5].
Sakatani et al. found patients with a high percentage of ventricular pacing (> 90%) had a higher incidence of cardiac events than patients with a low percentage of ventricular pacing (< 10%) [6]. In contrast, Shurrab et al. concluded from a meta-analysis that reduction in unnecessary ventricular pacing failed to affect hard clinical outcomes in patients with preserved left ventricular function [7]. Hence, the relationship between the pacing percentage and clinical outcomes is necessary to be further studied. In the present study, we evaluated whether the pacing percentage in patients with DDD implantation was a useful parameter in prediction overall and cardiovascular mortality.

Study Protocols and Design
The patients with a DDD pacemaker implantation who visited the pacemaker follow-up clinic for a checkup in a regional hospital in southern Taiwan since April 2016. We consecutively enrolled all the patients at their rst outpatient visit for regular pacemaker follow-up after their devices implantation. Exclusion were patients with malignancy. Finally, 177 patients were included in the present study. The study protocols were approved by the institutional review board committee of the Kaohsiung Medical University Hospital.

Measurements of devices parameters during follow-up visit
During the follow-up visit, we examined generator and leads status, including sensing, pacing threshold, impedance and percentage of sensing and pacing of atrial and ventricular leads. In particular, in order to decrease the percentage of ventricular pacing, we prolonged the PR interval to 20-30 ms longer than the intrinsic PR interval in patients with delayed AV conduction.
Collection of basic characteristics, medical, and laboratory pro les Basic characteristics including age, gender, and comorbid conditions were acquired from medical records or interviews with our patients [8]. Blood samples were obtained within 3 month of enrollment. The diagnosis of diabetes mellitus and hypertension were de ned by our previous study [8].

Collection of mortality data
Overall and cardiovascular mortality data were collected up to December 2019. All participants' mortality data were released from the Collaboration Center of Health Information Application, Ministry of Health and Welfare, Executive Yuan, Taiwan.

Statistical analysis
Result data were presented as mean ± standard deviation or percentage. Time to mortality events were modeled using the Cox proportional forward hazards models. All tests were 2-sided and their signi cance was de ned as P < 0.05. All statistical analyses were performed by SPSS 22.0 software (SPSS, Chicago, IL, USA).

Baseline characteristics among study patients
The baseline characteristics of 177 study subjects are shown in Table 1. The mean age was 72 ± 14 years. The most common indication for pacemaker implantation was sick sinus syndrome, regarding 48% of the patients (81 cases). Advanced AV block, including Mobitz type II 2nd degree AV block, highdegree AV block, and 3rd degree AV block was the next in frequency, regarding 44% of the patients (78 cases). During pacemaker follow-up, the percentages of atrial sense ventricular sense (ASVS), atrial sense ventricular pace (ASVP), atrial pace ventricular sense (APVS), and atrial pace ventricular pace (APVP) were 32 ± 37%, 33 ± 40%, 24 ± 33%, and 11 ± 20%, respectively.

Major predictors of overall and cardiovascular mortality in study patients
The follow-up period to mortality was 2.4 ± 1.0 years in all patients. Mortality events were documented during the follow-up period, including total mortality (n = 22) and cardiovascular mortality (n = 10). Table 2 shows the predictors of total mortality using Cox proportional hazards model. In the univariable analysis, increased total mortality was associated with increased age and decreased hemoglobin. After multivariable analysis, old age (hazard ratio [HR], 1.057; 95% con dence interval [CI], 1.006-1.112; P = 0.030) and low hemoglobin (HR, 0.753; 95% CI, 0.612-0.927; P = 0.007) were still the predictors of increased total mortality. All of sensing and pacing percentages were not correlated to increased total mortality. In addition, the percentage of total right ventricular pacing (ASVP + APVP) was also not correlated to total mortality (P = 0.429). Table 3 shows the predictors of cardiovascular mortality using Cox proportional hazards model. In the univariable analysis, increased cardiovascular mortality was associated with increased creatinine and high percentage of APVP. However, the percentage of total right ventricular pacing (ASVP + APVP) was not correlated to cardiovascular mortality (P = 0.182).After multivariable analysis, increased creatinine (HR, 1.385; 95% CI, 1.045-1.835; P = 0.023) and high percentage of APVP (HR, 1.030; 95% CI, 1.012-1.049; P = 0.001) were still the predictors of increased cardiovascular mortality.
This study aimed to evaluate pacing percentage in predicting total and cardiovascular mortality in patients with a DDD pacmeaker implantation. We found old age and low hemoglobin were associated with increased total mortality, but all of sensing and pacing percentages were not associated with total mortality. In contrast, in addition to high creatinene, high percentage of APVP was signi cantly assoicated with increased cardiovascular mortality after multivariable analysis.
Compared to single-chamber ventricular pacemaker, DDD pacemaker has an important advantage because it more closely resembles cardiac physiology by maintaining AV synchrony. Hence, it might decrease cardiovascular morbidity and mortality, and may prolong survival and improve quality of life [4,5]. Hence, in recent real-world practice, DDD pacemaker is a favor one unless patients have permanent atrial brillation. In patients with a DDD pacemaker, excessive right ventricular pacing may have an negative impact on cardiac function. Thus, it is necessary to optimize pacing parameters to mimize right ventricular pacing and maintain the cardiac function after pacemaker implant. In the study included patients with a DDD pacemaker by Zheng et al., subjects with a cumulative right ventricular percentage > 40% would have a more deterioation of cardiac function than those with a cumulative right ventricular percentage ≤ 40% [8]. In the study of Sakatani et al. included 268 consecutive patients with permanent pacemakers, they also found patients with a high percentage of ventricular pacing (> 90%) had a higher incidence of cardiac events than patients with a low percentage of ventricular pacing (< 10%) [6]. In contrast, Shurrab et al. demonstrated ventricular pacing reduction modalities did not improve clinical outcomes and were not superior to standard DDD programming in reducing incidence of permanent atrial brillation, all-cause hospitalization, or all-cause mortality [7]. In the present study, we similarly found the percentage of total right ventricular pacing (ASVP + APVP) was not correlated to total and cardiovascular mortaltiy.
APVP pacing mode has been considered inadequate in patients with a high degree of AV block and concomitant ischaemic heart disease. The possible explanation for this view was a fear of aggravating angina pectoris by a rate-dependent increase in myocardial oxygen consumption [9]. In addition, during ASVP pacing mode, both atria are activated via the intrinsic conduction system, but during APVP pacing mode, pacing of right atrial appendage resulted in a delayed electrical and mechanical activation of left atrium [10]. Hence, in the study of Bernheim et al., they found compared to ASVP pacing mode, APVP pacing mode could signi cantly worsen the myocardial performance index of left ventricle [11]. In the presen study, although the percentage of total right ventricular pacing was not a predictor of total and cardiovascular mortaltiy, the increased percentage of APVP was correlated to increased cardiovascular mortality. This nding implied that compared to ASVP pacing mode, APVP pacing mode might have a more deleterious impact on cardiovascular mortality. Therefore, reduction in unnecessary atrial and ventricular pacing in patients with a DDD pacemaker might be useful in improving cardiovascular prognosis.

Study limitation
There were several limitations in this study. First, the study generality was limited because our study patients were only included from one pacemaker follow-up clinic in a regional hospital in southern Taiwan. Second, our study was designed to assess the mortality events, so non-fatal events were not studied. Finally, the sample size of our study was relatively small, so the possibility of chance nding and the restricted power should be considered.

Conclusions
In patients with a DDD pacemaker, we found old age and low hemoglobin were associated with increased total mortality, but all of sensing and pacing percentages were not associated with total mortality. Besides, in addition to high creatinene, high percentage of APVP was signi cantly associated with increased cardiovascular mortality after multivariable analysis. Hence, reduction in unnecessary atrial and ventricular pacing in patients with a DDD pacemaker might be useful in improving cardiovascular prognosis.

Declarations
Ethics approval and consent to participate The study protocols were approved by the institutional review board committee of the Kaohsiung Medical University Hospital. Written informed consent was obtained from all subjects.

Consent for publication
Not applicable

Availability of data and material
All data that support the present ndings are included in our study. The datasets in the current study are available from the corresponding author on reasonable request.

Competing interests
The