Impact of a poor functional capacity on the clinical outcomes in patients with a pacemaker implantation –Results from the Japanese Heart Rhythm Society Registry –

Abstract Background Functional capacity (FC) correlates with mortality in various cardiovascular diseases. The aim of this study was to examine whether cardiac pacemaker implantations improve the FC and affect the prognosis. Methods and Results We prospectively enrolled 621 de novo pacemaker recipients (age 76 ± 9 years, 50.7% male). The FC was assessed by metabolic equivalents (METs) during the implantation and periodically thereafter. The patients were a priori classified into poor FC (<2 METs, n = 40), moderate FC (2 ≤ METs < 4, n = 239), and good FC (≥4 METs, n = 342). Three months after the pacemaker implantation, poor FC or moderate FC patients improved to a good FC by 43%. The distribution of the three FCs remained at those levels until after 1 year of follow‐up (P = .18). During a median follow‐up of 2.4 years, 71 patients (11%) had cardiovascular hospitalizations and 35 (5.6%) all‐cause death. A multivariate Cox analysis revealed that a poor FC at baseline was an independent predictor of both cardiovascular hospitalization (hazard ratio [HR] 2.494, P = .012) and all‐cause death (HR 3.338, P = .016). One year after the pacemaker implantation, the eight who remained with a poor FC had a high mortality rate of 37.5% (P < .01). Conclusion Approximately half of the poor or moderate FC patients improved to good FC 3 months after the pacemaker implantation. The baseline FC predicted the prognosis, and patients with an improved FC after the pacemaker implantation had a better prognosis.


| INTRODUC TI ON
Patients with bradyarrhythmias undergo ≈1 million de novo pacemaker implantations annually worldwide. 1 Since the first pacemaker implantation almost 60 years ago, permanent cardiac pacemaker therapy has evolved remarkably, becoming a minimally invasive treatment, improving the quality of life and reducing the mortality. [1][2][3] Device implantations are now indicated not only for young and middle-aged individuals who need to maintain physical activity, but also for elderly patients and those with a reduced physical function.
There is wide recognition that the functional capacity (FC) in patients with various cardiovascular diseases is an important risk factor for worsening heart failure and an increased risk of mortality, 4,5 however, there are limited data on whether pacemaker implantations improve the FC, and whether changes in the FC affect the outcomes.
In Japan, there is a system that exempts patients with serious diseases from medical expenses as handicapped disabled patients.
In the case of patients with an initial pacemaker implant, the handicapped disability levels can be divided into three levels depending on the indication of the pacemaker implantation defined by the Japanese Circulation Society 6 and their FC is determined by the metabolic equivalents (METs). Currently, three years after implanting a pacemaker, the disability level is recertified based on the FC at that time.
However, it is not known how the FC changes over time after the initial pacemaker implantation, and therefore, the optimal time for the recertification should be determined by prospective studies. Therefore, the aim of this study was to examine the temporal trends in the FC after a pacemaker implantation and the relationship between the FC and prognosis in patients receiving a de novo pacemaker implantation.

| Study population
This registry was a prospective, multicenter registry enrolling patient receiving de novo pacemaker implantations at 28 centers in Japan from April 2015 to September 2016. We enrolled patients who were at least 20 years old and had a pacemaker indication according to the Japanese guidelines. We excluded patients who refused to participate in this study. The protocol of this study was approved by the Ethics

Committee of the University of Occupational and Environmental
Health in Kitakyushu, Japan (H26-221). Informed consent was obtained from all patients prior to participation, and the study protocol was approved by each institutional Human Investigations Committee. The investigation was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments.

| Data collection and definitions
The patient characteristics and baseline and follow-up data were obtained through a review of their hospital charts. The anonymized patient data were collected in spreadsheet format by the physicians or clinical research coordinators at each institution. We examined the demographics, etiology of the pacemaker implantation, class of the JCS guideline indication, 6 and history of heart failure. The history of heart failure was determined as acute heart failure or worsening of chronic heart failure requiring hospitalization. The FC was estimated from the interview of the activities of daily living using a questionnaire 7 translated into Japanese by the National Institute of Health and Nutrition. 8

| Follow-up and endpoints
After the implantation, the patients were followed-up at each hospital once every few months for 6 months, and thereafter once every 6 months. The FC was recorded at 3 months, 6 months, 1 year, 2 years, and 3 years after the pacemaker implantation. The endpoints were cardiovascular hospitalization and all-cause mortality.

| Statistical analysis
Continuous variables are expressed as the mean ± SD or median with the interquartile range. Continuous variables were compared with a Student's t test. Categorical variables and the distribution of the FCs were analyzed using chi-squared test. Univariate and multivariate analyses with a Cox proportional hazard regression model was used to identify the significant predictors of the outcomes. The multivariate Cox proportional hazard analysis was adjusted for the age, gender, and significant variables in the univariate analyses, and a history of heart failure and atrial fibrillation.
The event-free curves were computed using the Kaplan-Meier method and compared with a log-rank test. A P < .05 was considered statistically significant. We used JMP version 11.0 software (SAS Institute Inc, Cary, NC, USA).    Kaplan-Meier analysis demonstrated that the rate of a hospitalization ( Figure 2A) and the total mortality were significantly higher as the FC decreased ( Figure 2B).    those that improved to good FC ( Figure 3B).

| D ISCUSS I ON
We examined the temporal trends in the FC and the relationship between the FC and prognosis in patients receiving an initial pacemaker  13 These data suggested that the device-measured physical activity may have served as a marker for the unmeasured factors contributing to the mortality risk. In addition, a novel chronotropic incompetence measure (Heart Rate Score) also predicts a worse outcome in patients who undergo device implantations. 14,15 Furthermore, Richards et al suggested that a blended sensor with minute ventilation and an accelerometer improves the Heart Rate Score in patients with pacemakers. 16 While these device built-in objective indicators may be useful to quantify an individual's activity, this device software has difficulty in interpreting because the measurement method and calculation method differ depending on the manufacturer. Additionally, device interrogation or remote monitoring are required to use these indicators. On the other hand, a subjective FC by a questionnaire, not a device-measured physical activity, is easily obtainable and is able to predict the outcome.
In this study we showed that 43% of the patients with poor or moderate FC at the time of the pacemaker implantation had improved FC 3 months after the implantation and improved FC was associated with a better outcome. Previous studies showed that the device-measured physical activity increased over a 30-day period after the implantation in patients that received an ICD or cardiac resynchronization therapy defibrillator. 13 That observation was consistent with our study, in that most of the patients had improved Importantly, a QOL improvement was similarly observed irrespective of the gender, presence of heart failure, or comorbidity level.
We suspected that the improved QOL with the pacemaker implantation may also have influenced the subsequent prognosis in this study.
To preserve or improve the physical activity after the permanent pacemaker implantation, physiological pacing is expected to be a   Our study showed that physical inactivity was associated with a poor survival independent of other risk factors. Cardiologists should pay attention not only to the device condition but also to encourage increased physical activity and to follow the patient compliance with physical activity recommendations. Considering the association between significantly reduced physical activity and a poor prognosis, individuals with an FC of <2 METs were stratified into serious conditions and required careful observation. In the majority of patients, the FC improved at 3 months after the pacemaker implantation and was maintained for at least 1 year. Patients with an improved FC at 1 year after the pacemaker implantation had a relatively good prognosis. Particularly, no patients died in the group with an improved FC (METs ≥ 4). Thus, a reevaluation of the physical disability between 3 months and one year after implantation gives the lowest percentage of poor FC.

| Study limitation
Our study included heterogenous patients receiving pacemakers for atrioventricular block, sick sinus syndrome, and atrial fibrillation with a slow ventricular response. We did not investigate the association between atrial or ventricular pacing frequency and prognosis. We did not investigate the detailed pacemaker pacing mode, pacing rate, heart rate distribution (ie, Heart Rate Score), or pacing site, therefore, the relationship between the pacemaker settings and physical activity could not be examined. However, irrespective of the device status, poor FC was proven to be useful as a prognostic indicator.
The conventional prognostic clinical tests such as the B-type natriuretic peptide, renal function, echocardiographic findings, and cardiopulmonary exercise testing were not analyzed. This study did not include the currently available leadless pacemakers.

| CON CLUS ION
The pacemaker implantation improved the FC in 43% of the patients with a poor or moderate FC at baseline and remained at that level to the end of 1 year. The poor FC (<2 METs) at baseline was significantly associated with a worse outcome. The patients whose FC improved at 1 year after the pacemaker implantation had a relatively good prognosis.