This was a single-center, randomized, controlled pilot study. Patients who required permanent PM implantation were candidates for the study. The exclusion criteria included patients for whom exercise was contraindicated, age over 75 years, achieved greater than 85% of the predicted maximal walking distance during the 6-minute walking test (6MWT) on the day following PM implantation, or refusal to participate. Finally, eligible patients were randomly assigned to either the CR or non-CR groups using computer-generated random permutation sequences.

Under intravenous anesthesia, an approximately 5 cm long incision was made in either the left or right upper chest, and a subcutaneous pocket was created. The unilateral axillary vein was punctured, followed by guidewire insertion. Thereafter, PM leads were advanced along the guidewires toward the right ventricle and/or right atrium depending on the type of PM. At the site representing the appropriate capture threshold, sensing value, and lead impedance, leads were screwed and the proximal ends were anchored tightly on the subcutaneous layer. The generator and leads were connected, and the generator was buried inside the pocket. After suturing the subcutaneous and cutaneous layers, hemostasis was performed by compression with gauze above the incision site overnight.

The patients in the CR group participated in hospital-based phase II rehabilitation, that is, the exercise training, while staff such as nurses and exercise physiologists monitor patients’ responses to exercise. The CR program was performed in an ambulatory setting, so all subjects in the CR group visited the training center in the hospital on schedule after discharge. They received exercise-based rehabilitation 8 times (3 times a week for the first 2 weeks and once a week for the next 2 weeks). CR programs were independent of the etiology of bradycardia and included personalized exercise and education. The 60-minute exercise program consisted of flexibility, aerobic, and resistance exercises based on the American Association of Cardiovascular and Pulmonary Rehabilitation guidelines [9]. To avoid PM lead displacement, the patients maintained the ipsilateral shoulder moving within a range of 90${}^{\circ }$ while performing the exercises. A lower-extremity recumbent ergometer was used for aerobic exercises with intensities of 55%–70% of the HR reserve. For resistance exercises, step-box workouts including step-ups, lateral step-overs, and squats were performed in 3 sets of 12–15 repetitions.

The 6MWT is a simple test to assess the submaximal level of functional capacity in a patient while walking on a flat, hard, and straight 30 m corridor for 6 min [10]. Patients were instructed to walk as far as possible. The 6-minute walking distance (6MWD) was defined as the measured distance during the 6MWT, changes in the 6MWD before and after each test, and resting and peak HRs during the exercise were measured. All participants completed the 6MWT on the subsequent day and were reassessed in the 4th week after PM implantation.

All patients underwent symptom-limited cardiopulmonary exercise tests (CPET) using electronically braked recumbent cycle ergometer testing (Quark CPET, Cosmed, Rome, Italy) with a continuous ramp (10 watts per 2 min) protocol. A real-time recording 12-channel electrocardiograph (Q-stress cardiac stress system, Quinton Instrument Co., Boston, MA, USA), a respiratory gas analyzer (Quark CPET, Cosmed, Rome, Italy), an automatic blood pressure (BP) and pulse monitor (Tango M2, Sun Tech Medical, Morrisville, NC, USA), and an ergometer (Angio CPET, Lode, Groningen, Netherlands) were used. The HR, BP, and Borg rating of perceived exertion (RPE) based on the 6–20 scale were recorded at the middle of each stage. The exercise test consisted of four phases: 3 min of rest, 3 min of unloaded cycling, ramp exercise, and recovery. The patients were encouraged to adopt a comfortable cadence, between 40 and 60 rpm throughout the test. The tests were terminated if the patients failed to maintain a cycle cadence of 40 rpm for more than one min despite encouragement or if the termination criteria were met [11].

Handgrip strength was assessed using a hand-held digital grip dynamometer (Jamar Hydraulic Hand Dynamometer; Sammons Preston Patterson Medical Products Inc., Bolingbrook, IL, USA) [12]. In a seated position with the elbow flexed at 90${}^{\circ }$, the patients were asked to squeeze the dynamometer as hard as possible to measure the maximum force exerted by each hand three times. Knee extension (KE) power was measured using a digital hand-held dynamometer (Jtech Medical, Salt Lake City, UT, USA) [13]. Patients sat in a chair with folded arms and knees bent at a 35${}^{\circ }$ angle. The best results from these three attempts were recorded.

QOL assessment was determined based on SF-36 scores. The SF-36 is a self-administered 36-item questionnaire consisting of two parts: the physical component summary (PCS) including general health, physical function, body pain, and role physical, and the mental component summary (MCS) including role emotion, social functioning, vitality, and mental health. The PCS and MCS scores are the sum of the four respective components. Each score was transformed to a scale of 0–100, with lower scores indicating greater disability (i.e., poor QOL).

The primary endpoint was any improvement in the physical function. Parameters included the 6WMD, handgrip strength, KE power, peak VO${}_2$, and ventilator equivalents of CO${}_2$ (VE/VCO${}_2$) as the values corresponding to functional capacities. The secondary endpoints included changes in PM parameters and improvements in QOL, as reflected by the SF-36 scores.

Continuous variables were tested for normal distribution. Normally distributed continuous variables were expressed as means and standard deviations. For those which did not, they were expressed as medians (interquartile range). Categorical variables were expressed as numbers and percentages. For inter- or intragroup comparisons, continuous variables were compared using the Student’s t test, Mann-Whitney U test, or Wilcoxon signed rank test, as appropriate and categorical variables were compared using Fisher’s exact test. Statistical significance was set at p 0.05. All statistical analyses were performed using SPSS version 21.0 (SPSS Inc., Chicago, IL, USA).

Of 113 consecutive patients who were scheduled to undergo new PM implantation, 75 patients were excluded as they were patients for whom exercise was contraindicated, were older than 75 years, or refused to participate. The remaining 38 patients underwent the 6WMT on the day following PM implantation, and 11 patients who achieved greater than 85% of the predicted maximal walking distance were also excluded. Finally, 27 patients (mean age 65.1 years, male 29.6%) were eligible for this study and randomly assigned to either the CR (n = 12, 44.4%) or non-CR (n = 15, 55.6%) groups. All the participants performed CPET, underwent measurements of muscle strength, and completed a QOL survey. Patients in the CR group received individualized exercise-based rehabilitation from the day following PM implantation for a total of 8 times. Meanwhile, those in the non-CR group visited a device clinic conventionally 2 weeks after the procedure. In the 4th week, the results of the 6MWT, CPET, muscle strength measurement, and SF-36 scores were obtained for all patients (Fig. 1).

Fig. 1.

Study protocol. Flow chart describes the number of patients who were eligible for the study, examinations at baseline and follow-up, and schedules for CR program.

The baseline characteristics and demographic data of the 2 groups are shown in Table 1. Despite the overall crossover rate of 22.2% (5 patients from CR to non-CR group and 1 patient from non-CR to CR group), mainly due to far distance to a rehabilitation center, there were no differences in comorbidities, medications, cardiac function, indications of PM implantation, or PM mode between both groups. Adherence to the rehabilitation program was 89.6% among the 12 patients in the CR group and 93.3% of patients in the non-CR group.

Fig. 2 compares the functional performance based on the 6MWT and muscle strength measurements at baseline and during follow-up in each group. As shown in Fig. 2A, the mean 6MWD increased significantly in both groups 4 weeks after PM implantation. There was no intergroup difference at baseline or during the follow-up period. Regarding muscle strength, KE power and handgrip strength did not differ between the groups (Fig. 2B,C).

Fig. 2.

Changes in physical performance in each group at baseline and during the follow-up period. (A) 6-minute walking distance, (B) knee extension power, and (C) handgrip strength. Data are represented as mean $\pm$ standard deviation.

Functional capacity measured based on peak VO${}_2$ increased from baseline, but there was no statistical significance in either group (Fig. 3A). The increase in the peak HR was significant only in the CR group (Fig. 3B). Other parameters, including the end-tidal partial pressure of carbon dioxide (P${}_{ET}$CO${}_2$), VE/VCO${}_2$, Borg RPE, respiratory exchange ratio (RER), and exercise duration, did not differ. There was neither desaturation nor arrhythmic events during the exercises in either group.

Fig. 3.

Cardiopulmonary exercise test. (A) Exercise capacity measured based on the peak oxygen uptake and (B) changes in peak heart rate during the exercises in each group at baseline and during the follow-up period. Data are represented as mean $\pm$ standard deviation.

Four weeks after PM implantation, statistically significant, but clinically insignificant subtle changes from baseline were found in p wave sensing and ventricular lead impedance in the CR group, and both lead threshold and ventricular lead impedance in the non-CR group (Supplementary Table 1). No intergroup differences were observed. During the exercises, no Wenckebach upper rate response or 2:1 conduction events occurred. Neither hematoma at the procedure site nor lead dislodgement was noted in any patient.

As shown in Table 2, only the CR group showed significant improvements in self-reported SF-36 scores in the items of vitality (42.1 $\pm$ 15.9 to 57.2 $\pm$ 15.4, p = 0.042) and mental health (50.3 $\pm$ 18.3 to 68.2 $\pm$ 22.4, p = 0.046). Meanwhile, no scores in the non-CR group demonstrated differences compared to baseline values.