Exercise-Based Cardiac Rehabilitation Improves Exercise Capacity Regardless of the Response to Cardiac Resynchronization Therapy in Patients With Heart Failure and Reduced Ejection Fraction

Abstract

Background: In patients with chronic heart failure with reduced ejection fraction (HFrEF), cardiac resynchronization therapy (CRT) improves left ventricular ejection fraction (LVEF) and exercise-based cardiac rehabilitation (ECR) enhances exercise capacity. This study examined the relationship between the 2 responses.

Methods and Results: Sixty-four consecutive HFrEF patients who participated in a 3-month ECR program after CRT were investigated. Patients were categorized according to a median improvement in peak oxygen uptake (PV̇O₂) after ECR of 7% as either good (n=32; mean percentage change in PV̇O₂ [%∆PV̇O₂]=23.2%) or poor (n=32; mean %∆PV̇O₂=2.5%) responders. There was no significant difference in baseline characteristics between the good and poor responders, except for PV̇O₂ (51% vs. 59%, respectively; P=0.01). The proportion of good CRT responders was similar between the good and poor responders (%∆LVEF ≥10%; 53% vs. 47%, respectively; P=NS). Overall, there was no significant correlation between %∆LVEF after CRT and %∆PV̇O₂ after ECR. Notably, among poor CRT responders (n=32), the prevalence of atrial fibrillation (0% vs. 29%; P<0.03) and baseline PV̇O₂ (48% vs. 57%; P<0.05) were significantly lower among those with a good (n=15) than poor (n=17) response to ECR.

Conclusions: In patients with HFrEF, good ECR and CRT responses are unrelated. A good PV̇O₂ response to ECR can be achieved even in poor CRT responders, particularly in those with a sinus rhythm or low baseline PV̇O₂.

Heart failure is a major public health problem and is associated with high morbidity and mortality.^1–3 In patients with chronic heart failure with reduced ejection fraction (HFrEF), cardiac resynchronization therapy (CRT) improves left ventricular ejection fraction (LVEF),^4–7 exercise capacity, and long-term survival.^5–9 Following CRT, patients’ LVEF increases by approximately 10% points and left ventricular (LV) end-diastolic volume decreases by 20%; these changes are associated with better long-term prognoses.¹⁰ However, up to 30% of patients show a poor response to CRT.¹¹ In these patients, LVEF does not improve after CRT.¹²

Editorial p ????

Exercise-based cardiac rehabilitation (ECR) improves exercise capacity and the quality of life (QOL) in patients with HFrEF, and reduces the rate of hospitalization due to any cause.^13,14 A meta-analysis showed that participation in an ECR program comprising moderate-intensity exercise increases patients’ exercise capacity (measured as peak oxygen uptake [PV̇O₂]) by approximately 13%.¹⁵ In addition, participation in ECR after CRT has been reported to improve patients’ PV̇O₂ and QOL.¹⁶ Therefore, cardiac rehabilitation is recommended by current heart failure practice guidelines at the Class I level.^1,17,18

A previous observational study reported that CRT responders with favorable LV reverse remodeling had an improved exercise capacity 6 months after CRT.⁹ However, this improvement, rather than being achieved through ECR, may have been the result of attenuation of heart failure symptoms after CRT. Therefore, it remains unknown whether good CRT responders also respond well to ECR after CRT. Furthermore, it remains unclear whether improvements in LVEF after CRT and enhanced exercise capacity after ECR are correlated.

Accordingly, the aim of the present study was to determine whether a good ECR response coincides with a good CRT response, and whether the percentage increase in exercise capacity, measured as the percentage change in PV̇O₂ (%∆PV̇O₂), after ECR is correlated with the percentage change in LVEF (%∆LVEF) after CRT.

Methods

Study Population

We retrospectively investigated 207 patients with HFrEF who participated in a 3-month ECR program after CRT between February 2003 and May 2017 at the National Cerebral and Cardiovascular Center, Japan. The study inclusion criteria were HFrEF with LVEF <35% and undergoing CRT (with or without a defibrillator). Patients who were implanted with left ventricular assist devices (n=6), participated in the ECR program ≥2 times during the study period (n=55), lacked cardiopulmonary exercise testing (CPX) data either at the beginning or end of the program (n=50), or dropped out of the 3-month ECR program (n=32) were excluded from the study. This left 64 patients who had completed the ECR program and had sufficient CPX data for inclusion in the study (Figure 1). Customized treatment for heart failure was provided to all patients based on current guidelines.

Figure 1.

Flowchart of patient selection. CPX, cardiopulmonary exercise testing; CRT, cardiac resynchronization therapy; ECR, exercise-based cardiac rehabilitation; LVAD, left ventricular assist device; V̇O₂, oxygen uptake.

This study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee at the National Cerebral and Cardiovascular Center, Japan (Reference number M26-015-2). The need for informed consent was waived with an opt-out procedure by the Ethics Committee due to the retrospective nature of the study.

Device Implantation and Programming

CRT was performed according to the standard pacemaker implantation technique. Briefly, pacemakers were programmed to a base rate of 60 or 70 beats/min and an upper limit 85% of the age–sex maximum predicted heart rate (HR). Atrioventricular delays and right-to-left ventricular activation delays were programmed to the optimum value by echocardiography. Biventricular DDDR pacemakers were implanted in patients with a sinus rhythm and biventricular VVIR pacemakers were implanted in those with atrial fibrillation (AF). Patients with AF did not undergo atrioventricular node ablation before or during the study period. CRT devices were implanted with or without defibrillator use, as appropriate, and no distinction was made between these patients in the data analysis.

ECR Program

Following CRT device implantation and medication adjustment (usually 2–3 weeks after CRT device implantation), the 3-month ECR program was initiated through supervised in-hospital sessions (5 days/week), followed by supervised out-patient sessions (1–3 times/week) combined with home exercise according to the Japanese Circulation Society guidelines.¹⁸

The ECR program predominantly comprised aerobic exercise, such as walking, cycling on an ergometer, and calisthenics, as well as home exercise (90–150 min/week). The intensity of the aerobic exercise was determined individually using one of the following: (1) 40–50% of the actual measured HR reserve (Karvonen formula, with K=0.4–0.5); (2) HR at the anaerobic threshold determined during CPX; or (3) HR at Level 12–13 (“somewhat hard”) on Borg’s Rating of Perceived Exertion Scale (total range, 6–20).¹⁹ Patients diagnosed as having physical deconditioning performed low-intensity resistance training, comprising standing calf raises and sit-to-stand exercises using their own body weight. Each exercise was performed for 7–10 repetitions per set, 3 sets per day, 2–3 times per week.

The ECR program also comprised educational classes (e.g., heart failure self-care, diet, salt restriction, blood pressure control, body weight control, and exercise recommendations) and individual counseling (e.g., anxiety, depression, and self-care).

CPX and Blood Sampling

Symptom-limited CPX was performed using a cycle ergometer with respiratory gas analysis at the beginning and end of the 3-month ECR program. The test comprised an initial 2 min of rest on a bicycle ergometer in the upright position, 1 min of warm up (0 W load), and then full exercise using an individualized ramp protocol with increments of 10 or 15 W/min. Expired gas analysis was performed throughout the CPX on a breath-by-breath basis, with minute ventilation (V̇E), oxygen consumption (V̇O₂), and carbon dioxide production (V̇CO₂) data were stored on a computer hard disk every 6 s for off-line analysis (AE-300S; Minato Medical Science, Osaka, Japan). The PV̇O₂ was determined as the highest V̇O₂ value (mL/min) achieved at peak exercise. The PV̇O₂ was adjusted for age, sex, and body weight (mL·kg⁻¹·min⁻¹) and expressed as a percentage of the predicted value (%pred-PV̇O₂) in the Japanese population according to a previous report.²⁰ Blood samples were drawn for standard biochemical measurements and plasma B-type natriuretic peptide (BNP) at the beginning and end of the ECR program. BNP was measured using a validated commercially available immunoassay kit (Tosoh, Tokyo, Japan).

Echocardiography

Echocardiographic examinations were performed using commercially available ultrasound machines (Toshiba Medical Systems, Tokyo, Japan; GE Healthcare, Milwaukee, WI, USA) at 3 time points: (1) before CRT implantation; (2) at ECR entry (usually 1–4 weeks after CRT implantation); and (3) approximately 6 months after CRT implantation. LV end-diastolic diameter (LVDd) was measured with 2-dimensional echocardiography and LVEF was measured by the modified biplane Simpson’s method, as recommended by the American Society of Echocardiography.²¹ %∆LVEF after CRT was determined as the percentage change from the value before to that 6 months after CRT. Good CRT responders were defined as those with %∆LVEF ≥10% after CRT.

Statistical Analysis

First, all 64 patients in the study were divided into 2 groups based on the median percentage increase in PV̇O₂ at the end of the 3-month ECR program of 7.0% into good (%∆PV̇O₂ ≥7.0%; n=32) and poor (%∆PV̇O₂ <7.0%; n=32) ECR responders (Figure 1). The patients’ baseline characteristics, CPX data after the 3-month ECR program, and the proportion of good CRT responders were compared between these 2 groups.

Second, the correlation between %∆PV̇O₂ after ECR and %∆LVEF after CRT was examined in all patients. Moreover, to clarify the clinical characteristics of patients in whom the response to ECR was good despite a poor CRT response, we compared the clinical characteristics of the good and poor ECR responders in the poor CRT responder group.

Data are expressed as mean±SD for normally distributed variables and as the median with interquartile range for non-normally distributed data. Categorical data are expressed as numbers and percentages. Comparisons between groups were performed using unpaired t-tests and χ² tests. Paired t-tests were used to compare the paired numerical variables before and after ECR, except for changes in BNP, which were evaluated using the non-parametric Wilcoxon signed-rank test. Statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan),²² which is a graphical user interface for R version 3.6.2 (R Foundation for Statistical Computing, Vienna, Austria). Two-sided P<0.05 was considered significant.

Results

Baseline Characteristics

In all, 64 patients treated between February 2003 and May 2017 who met the inclusion criteria were enrolled in the study. The baseline characteristics of all patients, as well as the good and poor ECR responders separately, are presented in Table 1. At baseline, the patients’ mean age was 62 years, and the sample showed male predominance (84%). There were no significant differences in baseline characteristics, including age, sex, comorbidities, medications, severity of LV dysfunction, and duration from CRT to ECR initiation, between the good and poor ECR responders. The only difference observed was a significant reduction in exercise capacity (i.e., peak work rate [WR]) and %pred-PV̇O₂ at the time of ECR initiation in the good vs. poor ECR responders. The mean peak respiratory exchange ratio at initial CPX was 1.30 in both groups, indicating that patients in both group exercised equally until exhaustion and that the PV̇O₂ data obtained are a reliable and valid measure of peak exercise capacity.

Table 1. Baseline Patient Characteristics at the Beginning of ECR Program

Characteristic	All patients (n=64)	Good ECR responders (n=32)	Poor ECR responders (n=32)	P value*
Age (years)	62±13	61±13	64±14	0.3929
Male sex	54 (84)	28 (88)	26 (81)	0.4899
BMI (kg/m2)	21.1±2.7	21.2±3.0	21.0±2.3	0.8569
Hypertension	30 (47)	13 (41)	17 (53)	0.3157
Diabetes	19 (29)	7 (22)	12 (38)	0.1713
Dyslipidemia	41 (64)	19 (59)	22 (69)	0.4340
IHD	29 (45)	13 (41)	16 (50)	0.4509
Chronic AF	8 (13)	2 (6)	6 (19)	0.1230
PAF	21 (33)	10 (31)	11 (34)	0.7901
LVDd (mm)	67±9	67±8	66±10	0.5643
LVEF (%)	23±8	23±8	24±8	0.3655
Hemoglobin (g/dL)	12.4±1.9	12.5±1.6	12.4±2.1	0.8018
Serum creatinine (mg/dL)	1.3±0.5	1.2±0.5	1.4±0.5	0.3916
BNP (pg/mL)	276 [150, 459]	317 [180, 489]	257 [114, 419]	0.3107
Complete LBBB	26/62 (42)	16/30 (53)	10/32 (31)	0.0771
QRS width (ms)	147±39 (n=61)	151±40 (n=31)	142±38 (n=30)	0.3705
Medications
β-blocker	62 (97)	32 (100)	30 (94)	0.0921
ACEI or ARB	46 (72)	23 (72)	23 (72)	1.0000
Diuretic	59 (91)	28 (88)	30 (94)	0.3869
Oral inotrope	15 (23)	10 (31)	5 (16)	0.1371
CPX parameters at ECR start
Resting HR (beats/min)	69±10	69±11	69±9	0.8684
Peak HR (beats/min)	109±25	108±28	110±21	0.8351
Peak RER	1.30±0.12	1.30±0.13	1.30±0.11	0.5782
Peak WR (W)	80±23	73±27	86±19	0.0390
Peak V̇O2 (mL·min−1·kg−1)	15.0±3.5	14.5±3.9	15.6±2.9	0.2021
Predicted PV̇O2 (%)	55±12	51±14	58±9	0.0292
AT	554±113 (n=53)	565±142 (n=23)	546±87 (n=30)	0.5424
V̇E-V̇CO2 slope	35.6±7.6	35.5±8.1	35.8±7.1	0.8973
Time from CRT to ECR (days)	23 [8, 134]	27 [7, 130]	21 [8, 141]	0.6198

Variables are expressed as the mean±SD, n (%), or median [interquartile range]. *For comparisons between good and poor ECR responders. ACEI, angiotensin-converting enzyme inhibitor; AF, atrial fibrillation; ARB, angiotensin receptor blocker; AT, anaerobic threshold; BMI, body mass index; BNP, B-type natriuretic peptide; CPX, cardiopulmonary exercise testing; CRT, cardiac resynchronization therapy; ECR, exercise-based cardiac rehabilitation; HR, heart rate; IHD, ischemic heart disease; LBBB, left bundle branch block; LVDd, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; PAF, paroxysmal AF; RER, respiratory exchange ratio; V̇CO₂, carbon dioxide production; V̇E, minute ventilation; V̇O₂, oxygen uptake; WR, work rate.

Changes in Variables After ECR and CRT

Over the cumulative 1,078 ECR sessions implemented in the 64 patients, no adverse events related to exercise (including death, life-threatening arrhythmias, appropriate or inappropriate implantable cardioverter-defibrillator shock, and lead dislocation) were observed during the study period. Table 2 presents between-group comparisons of ECR session attendance, BNP, and CPX data after 3 months of ECR, LVEF before and 6 months after CRT, and changes from respective baselines. Among all patients, at the end of the 3-month ECR program, measures of exercise capacity (i.e., peak WR, PV̇O₂, and %pred-PV̇O₂) increased significantly from their respective baseline values (all P<0.01). In addition, LVEF at 6 months after CRT among all patients increased significantly compared with before CRT (P<0.01), with an absolute change in LVEF (∆LVEF) of 3±7% and a %∆LVEF of 17±37%. Of note, although BNP was unchanged at 3 months for the entire patient cohort, it decreased significantly from 317 to 248 pg/mL (P<0.05, Wilcoxon signed-rank test) in good ECR responders and increased slightly in poor ECR responders (from 257 to 305 pg/mL; NS).

Table 2. Changes in the Major Variables During the 3-Month ECR Program or 6 Months After CRT

Variables	All patients (n=64)	Good ECR responders (n=32)	Poor ECR responders (n=32)	P value*
ECR attendance (no. sessions)	19±11	20±12	18±10	0.5021
Hemoglobin (g/dL)
At 3 months	13.2±1.5	13.3±1.4	13.0±1.7	0.6953
Change from baseline	0.7±1.5	0.8±1.3	0.6±1.7	0.5315
Serum creatinine (mg/dL)
At 3 months	1.3±0.5	1.3±0.5	1.3±0.5	0.7062
Change from baseline	0.0±0.3	0.1±0.3	0.0±0.2	0.7586
BNP (pg/mL)
At 3 months	261 [143, 474]	248 [147, 489]	305 [141, 458]	0.7780
Change from baseline	−14 [−102, 72]	−40 [−120, 29]	6 [−100, 147]	0.0707
Resting HR (beats/min)
At 3 months	68±8	69±10	67±7	0.4897
Change from baseline	−1±6	−1±6	−1±8	0.9212
Peak HR (beats/min)
At 3 months	109±25	109±22	107±25	0.6425
Change from baseline	−1±15	−0±15	−2±14	0.6416
Peak RER
At 3 months	1.27±0.12	1.29±0.12	1.25±0.12	0.2040
Change from baseline	−0.01±0.10	0.00±0.11	−0.02±0.09	0.3998
Peak WR (W)
At 3 months	87±24	90±29	85±18	0.3566
Change from baseline	8±13	17±10	−1±9	<0.0001
PV̇O2 (mL·min−1·kg−1)
At 3 months	16.0±3.7	17.2±4.5	14.9±2.6	0.0137
Change from baseline	1.0±1.7	2.8±0.3	−0.7±0.3	<0.0001
% Predicted PV̇O2 (%)
At 3 months	58±12	61±16	56±8	0.0741
Change from baseline	4±6	10±7	−2±4	<0.0001
AT
At 3 months	597±140 (n=57)	629±155 (n=28)	567±118 (n=29)	0.0912
Change from baseline	41±87 (n=48)	64±93 (n=20)	25±80 (n=28)	0.1266
V̇E-V̇CO2 slope
At 3 months	35.9±6.8	34.9±7.7	36.7±5.8	0.2932
Change from baseline	0.2±5.2	−0.6±5.5	1.0±5.5	0.2320
LVEF before and 6 months after CRT (%)
Before CRT	23±7	23±7	23±7	0.8071
At 6 months after CRT	26±8	26±9	25±7	0.7618
Change at 6 months	3±7	3±7	3±8	0.9081

Variables are expressed as the mean±SD or median [interquartile range]. *For comparisons between good and poor ECR responders. PV̇O₂, peak oxygen uptake. Other abbreviations as in Table 1.

Figure 2 shows the percentage change in peak WR (%∆peak WR) and %∆PV̇O₂ after ECR, and the %∆LVEF after CRT in the good and poor ECR responders. At 3 months, both %∆peak WR (+28.6% vs. −0.69%; P<0.001) and %∆PV̇O₂ (+23.2% vs. −2.5 %; P<0.001) were significantly higher in the good ECR responders. However, there was no significant difference between the 2 groups in %∆LVEF after CRT (+14.4% vs. +18.7 %; NS; Figure 2). Furthermore, the proportion of CRT responders did not differ significantly between good and poor ECR responders (53% vs. 47%, respectively; Figure 3). There were no significant correlations between %∆peak WR and %∆LVEF (Figure 4A; r=0.017, NS) and %∆PV̇O₂ and %∆LVEF (Figure 4B; r=0.013, NS).

Figure 2.

Comparison of percentage changes in (A) peak work rate (%∆peak WR) and (B) peak oxygen uptake (%∆PV̇O₂) after 3 months of exercise-based cardiac rehabilitation (ECR), and (C) percentage change in left ventricular ejection fraction (%∆LVEF) 6 months after cardiac resynchronization therapy (CRT) in good and poor ECR responders. Data are presented as the mean±SEM.

Figure 3.

Comparison of the proportions of cardiac resynchronization therapy (CRT) responders between good and poor exercise-based cardiac rehabilitation (ECR) responders.

Figure 4.

Correlations between percentage changes in (A) peak work rate (%∆peak WR) and (B) peak oxygen uptake (%∆PV̇O₂) after exercise-based cardiac rehabilitation (ECR) and left ventricular ejection fraction (%∆LVEF) after cardiac resynchronization therapy (CRT).

Differences Between Good and Poor ECR Responders Among Poor CRT Responders

To determine the clinical features of good ECR responders with a poor CRT response, we compared baseline characteristics at ECR initiation and ECR session attendance between the good (n=15) and poor (n=17) ECR responders among the 32 patients with a poor CRT response (Table 3). There was no significant difference between the 2 groups in most clinical characteristics, medications, %∆LVEF after CRT, and ECR attendance. However, the good ECR responders had a significantly lower prevalence of chronic AF and lower baseline %pred-PV̇O₂ than poor ECR responders.

Table 3. Features of Good and Poor ECR Responders With a Poor CRT Response

Characteristic	All poor CRT responders (n=32)	Good ECR responders (n=15)	Poor ECR responders (n=17)	P value*
Age (years)	60±14	56±13	63±14	0.1723
Male sex	28 (88)	14 (93)	14 (82)	0.3486
BMI (kg/m2)	21.2±3.0	21.8±3.4	20.6±2.5	0.2700
Hypertension	13 (41)	5 (33)	8 (47)	0.4302
Diabetes	9 (28)	3 (20)	6 (35)	0.3369
Dyslipidemia	21 (66)	8 (53)	13 (76)	0.1691
IHD	16 (50)	6 (40)	10 (59)	0.2879
Chronic AF	5 (16)	0 (0)	5 (29)	0.0222
LVDd (mm)	67±9	68±7	68±10	0.8759
LVEF (%)	24±8	23±10	25±7	0.5076
BNP (pg/mL)	262 [150, 534]	312 [167, 621]	258 [116, 465]	0.3310
Complete LBBB before CRT	11/30 (37)	6/13 (46)	5/17 (29)	0.3457
QRS width before CRT	143±40 (n=29)	147±43 (n=14)	139±37 (n=15)	0.6106
Medications
β-blocker	30 (94)	15 (100)	15 (88)	0.4859
ACEI or ARB	22 (69)	12 (80)	10 (59)	0.1972
Diuretic	28 (88)	13 (87)	15 (88)	0.8935
Inotropic	9 (28)	6 (40)	3 (18)	0.1605
CPX parameters at ECR entry
Resting HR (beats/min)	69±8.6	69±8.5	69±8.9	0.9205
Peak HR (beats/min)	110±21	107±17	112±24	0.4814
Peak RER	1.3±0.13	1.3±0.15	1.2±0.11	0.0998
Peak WR (W)	78±24	71±25	83±22	0.1570
Peak V̇O2 (mL·min−1·kg−1)	15.1±3.8	14.4±4.1	15.7±3.4	0.3323
Predicted peak V̇O2 (%)	53±13	48±15	57±10	0.0455
AT	546±111 (n=26)	553±143	542±90	0.8136
V̇E-V̇CO2 slope	36.6±8.2	37.5±8.5	35.9±8.0	0.5930
ECR attendance (no. sessions )	17±11	19±12	16±10	0.4629

Variables are expressed as the mean±SD, n (%), or median [interquartile range]. *For comparisons between good and poor ECR responders. Abbreviations as in Table 1.

Discussion

Major Findings

In the present study we found that, among patients with HFrEF who had undergone CRT and were receiving optimal medical therapy: (1) a good PV̇O₂ response to ECR did not coincide with a good LVEF response to CRT; (2) %∆PV̇O₂ after ECR was not correlated with %∆LVEF after CRT; and (3) a good response to ECR can be expected even in poor CRT responders, especially in those with a sinus rhythm or low baseline PV̇O₂. These findings suggest that the PV̇O₂ response to ECR and the LVEF response to CRT are independent of each other, and severe heart failure patients undergoing CRT implantation can experience improved exercise capacity through ECR, regardless of the degree of improvement in LVEF after CRT.

Previous Studies

Patwala et al¹⁶ reported that the addition of exercise training after CRT increased exercise capacity in patients with chronic heart failure, but these authors did not investigate the relationship between the CRT response and PV̇O₂ improvement. Mastenbroek et al⁹ found that CRT responders had an improved exercise capacity compared with non-responders 6 months after CRT, and concluded that there was a significant positive association between LV reverse remodeling and exercise capacity after CRT. However, this improvement in exercise capacity was a natural consequence of CRT implantation rather than an ECR response. Thus, the present study is the first to investigate the relationship between CRT response and ECR response, as well as the relationship between %∆LVEF after CRT and %∆PV̇O₂ after ECR.

Mechanisms Underlying the Present Findings

The finding in the present study that the CRT response and ECR response are unrelated may be explained by the difference in the mechanisms underlying the 2 treatments. Although CRT primarily enhances LV contractility and increases cardiac output by reducing the degree of cardiac dyssynchrony (i.e., a central mechanism),⁵ ECR increases exercise capacity in patients by improving endothelial function and skeletal muscle metabolism and mitigating neurohormonal derangement and cytokine production (i.e., mainly peripheral mechanisms).^23–25 It is of interest whether these mutually independent mechanisms may have synergistic or counteracting effects in patients with heart failure. In this context, it is intriguing significant decreases in BNP were seen in good, but not poor, ECR responders.

Another novel finding of the present study is that the good ECR responders with a poor CRT response had a lower prevalence of chronic AF and lower baseline PV̇O₂ than the poor ECR responders. This suggests that poor CRT responders with chronic AF or high baseline PV̇O₂ may respond poorly to ECR. In terms of chronic AF, a subanalysis of the HF-ACTION (Heart Failure: A controlled Trial Investigating Outcomes of Exercise Training) trial reported that the degree of increase in PV̇O₂ with exercise training was similar in HFrEF patients with and without AF;²⁶ however, the findings of that subanalysis require cautious interpretation, because the increases in PV̇O₂ following exercise training were not significantly different from baseline to 3 months in either the AF or non-AF group because of the low level of adherence to exercise training in that trial. Conversely, Abreu et al reported that heart failure patients with AF experienced a greater increase in PV̇O₂ after CRT than those with a sinus rhythm.²⁷ Further studies are needed to explore the difference in the PV̇O₂ response to ECR between poor CRT responder HFrEF patients with chronic AF and those with a sinus rhythm.

Regarding baseline PV̇O₂, it is known that lower baseline exercise capacity is an important predictor of greater improvements in exercise capacity after ECR.^28,29 This was confirmed in the present study in poor CRT responders with reduced exercise capacity.

Clinical Implications

The findings of the present study have several clinical implications. First, they suggest that ECR should be recommended to all patients after CRT, because ECR can safely increase patients’ exercise capacity independent of their CRT response. Second, the findings highlight the importance of ECR in poor CRT responders with a sinus rhythm or low PV̇O₂ values, because, in these patients, a substantial increase in PV̇O₂ is expected with ECR in the absence of LVEF improvements after CRT. Third, for poor CRT responders with chronic AF or preserved PV̇O₂ at ECR initiation, exercise prescription modifications (e.g., the addition of resistance training or high-intensity interval training) should be considered to effectively increase their exercise capacity.

Study Limitations

The present study has several limitations. First, it was a retrospective single-center study with a small sample size. In addition, the patients were relatively young and predominantly not obese. Further studies with a larger number of patients should be performed to examine the generalizability of our findings. Second, because this study did not include a control group that did not participate in ECR, it could be argued that the improvements in exercise capacity could be attributable to the natural disease course after CRT. However, Nobre et al reported that, without exercise training, PV̇O₂ increased by only 2.6% (not statistically significant) from 1 to 5 months after CRT.³⁰ Furthermore, it would be unethical to assign patients with HFrEF to a non-ECR group at present when ECR is strongly recommended in the heart failure guidelines.^1,17,18

Third, there could be a concern about a possible interaction between the effects of CRT and ECR, because the timing of the assessment of %∆LVEF and %∆PV̇O₂ in the present study overlapped. However, because the improvement in LVEF after ECR was reported to be small in a meta-analysis,³¹ and because there was no correlation between %∆peak WR and %∆LVEF or %∆PV̇O₂ and %∆LVEF in the present study, we consider that the interaction between the effects of CRT and ECR on LVEF, if any, would be negligible.

Fourth, the increase in PV̇O₂ in the present study (1.0±1.7 mL·kg⁻¹·min⁻¹, or a median of 7%) seems relatively small. However, this increase in PV̇O₂ is comparable to that in CRT patients in the HF-ACTION trial (1.1 mL·kg⁻¹·min⁻¹).³² In addition, a subanalysis of HF-ACTION reported that every 6% increase in PV̇O₂ was associated with an improved long-term prognosis.³³ Therefore, the seemingly small increase in PV̇O₂ in the present study may be clinically meaningful. Finally, we did not assess the patients’ nutritional status or skeletal muscle function in the present study, although both these factors may have influenced the improvements in exercise capacity. It is important to assess these factors because the number of elderly patients with heart failure and frailty is rapidly increasing.

Further studies are needed to investigate the predictors of improvements in exercise capacity following ECR and the optimal exercise prescription in patients with heart failure after CRT.

Conclusions

In patients with HFrEF after CRT implantation, a good PV̇O₂ response to ECR does not coincide with a good LVEF response to CRT, and the %∆PV̇O₂ after participating in a 3-month ECR program is not correlated with the %∆LVEF after CRT, indicating that the PV̇O₂ response to ECR and the LVEF response to CRT are independent of each other. Furthermore, a good ECR response can be achieved even in poor CRT responders, especially those with a sinus rhythm or low baseline exercise capacity.

Acknowledgments

The authors thank Editage for English language editing a version of this manuscript.

Sources of Funding

This study did not receive any specific funding.

Disclosures

The authors declare that there are no conflicts of interest.

IRB Information

The study was approved by the Ethics Committee of the National Cerebral and Cardiovascular Center (Reference number M26-015-2).

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