Congenital heart disease (ConHD) accounts for nearly one-third of all major congenital anomalies.1 With an accompanying increase in health care usage, the number of adults with congenital heart disease (ACHD) is projected to continue to grow in the coming years.2 However, depending on the existing underlying defects, substantial segments of ACHD remain symptomatic, with significantly impaired exercise capacity despite receiving optimal medical therapy3; in addition, these patients might be exposed to risk factors for coronary artery disease and the adverse consequences of a sedentary lifestyle such as obesity and hypertension.4 A longitudinal study showed a progressive decline in the natural history of exercise capacity in many types of ConHD patients,5 and impairment of exercise capacity has been shown to be reduced by up to 50% even in patients with simple lesions.6 Decreased exercise capacity is also considered to be an independent predictor of death or hospitalization for ACHD.7
Regardless of the extent, the observed significant decline in exercise capacity in most ACHD might be related not only to pathophysiological mechanisms but also to self-overprotection based on health misconceptions,8 which are common barriers to regular physical activity and worsen as a result of sedentary lifestyle. Strong evidence shows that physical inactivity increases the risk of many adverse health conditions.9 Low cardiorespiratory fitness, in addition to elevated systolic blood pressure, smoking, obesity, and diabetes, has been demonstrated to be an important risk factor for increased mortality.10 On the contrary, exercise confers a variety of important health benefits, including beneficial effects on hypertension and endocrine and metabolic health.11 Exercise also has been described as one of the most cost-effective methods of decreasing morbidity and mortality associated with cardiovascular disease,12 and its multiple specific health benefits have been reported in heart failure,13 coronary artery disease,14 and pulmonary and systemic hypertension.15
American and European ACHD guidelines have recommended that some form of exercise should be encouraged in this population.16,17 These recommendations are mostly based on expert opinion, because evidence related to the effects of exercise training in ACHD is scarce. Despite previous reviews describing exercise as a beneficial treatment in ACHD,18,19 no meta-analysis has been performed to investigate the effects of exercise training in ACHD. The aim of this systematic review with meta-analysis was to analyze the published trials that investigated the effects of exercise training on cardiorespiratory fitness and other health parameters in ACHD.
LITERATURE SEARCH AND SELECTION CRITERIA
This meta-analysis was conducted adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.20 Search terms such as “congenital heart defect,” “congenital heart disease,” “physical activity,” and “exercise” were searched through 5 databases, including PubMed, EMBASE, the Cochrane Library, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Web of Science for trials reporting the effect of exercise training in ACHD published up to January 2018. An English language restriction was imposed. Two independent reviewers (K.S. and Q.D.) carried out the initial search, deleted duplicate records, screened the titles and abstracts for relevance, and identified each as excluded or requiring further assessment. The full-text articles designated for inclusion were reviewed, and the references of the retrieved articles and previous reviews were manually checked to identify additional eligible studies.
Studies were included according to the following criteria: (1) ConHD patients with clinical diagnosis, without surgery or with previous cardiac surgery >12 mo before, and individuals older than 18 yr; (2) any type of exercise training; (3) no intervention or other interventions except exercise; (4) primary outcome was cardiorespiratory fitness reported as peak oxygen uptake (peak
O2), maximal workload, and maximal exercise duration during a cardiopulmonary exercise test; (5) secondary outcomes were neurohumoral activation reported as N-terminal of probrain natriuretic peptide (NT-proBNP) levels, the rating of perceived exertion (RPE) measured by the Borg rating of perceived exertion (Borg RPE) scale, and safety information; and (6) randomized controlled trial or nonrandomized controlled trial and observational studies (including both prospective and retrospective cohort studies).
DATA EXTRACTION AND QUALITY ASSESSMENT
Data extraction was performed by 1 of the researchers (X.L.) and confirmed independently by another reviewer (N.C.). The following information was extracted from each study: first author, year of publication, study design, number of participants enrolled (% male), patient characteristics, medications used, and outcome data. Exercise training and control group interventions in parallel group trials, as well as exercise training interventions used in the included pre- and post-intervention or cohort studies, were also extracted. When the same patients were reported in several publications, we retained only the 1 with the largest sample size to avoid duplication of information. Discrepancies were resolved through a consensus discussion with a third reviewer (X.Z.), if necessary. The methodological quality of the studies was assessed using the Cochrane Risk of Bias Tool21 or the Newcastle Ottawa Scale case-control and cohort tools.22
STATISTICAL ANALYSIS AND DATA SYNTHESIS
We analyzed the effects of exercise training on outcomes of interest, using Review Manager (RevMan 5.3). Synthesis of the data was performed using the random-effects model if 2 or more trials evaluated the same outcome in comparable groups. The control conditions in controlled studies and cohort studies included both no treatment and other treatments, including general treatment, education, and no exercise treatment. If 2 or more control groups performed various treatments in 1 trial, the data from the control groups were combined, using the process suggested in the Cochrane handbook.21 If the published reports of clinical studies report only the median, interquartile range, and the size of the trial, we used simple and elementary inequalities and approximations to estimate the mean and the variance for each study.23 The results at baseline and after exercise training in the pre- and post-intervention studies were simply considered as 2 independent groups for the meta-analysis. The subgroup analyses were performed only for parallel group trials. Differences were expressed as the mean difference (MD) with 95% CI. Heterogeneity across studies was tested with the I2 statistic. Studies with an I2 statistic of <25% were considered to have no heterogeneity, 25% to 50% were considered to have low heterogeneity, 50% to 75% were considered to have moderate heterogeneity, and those with an I2 statistic of >75% were considered to have high heterogeneity.24
All corresponding authors were contacted to provide the provision of any unreported data, which was required for our meta-analysis. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system provides grading criteria for assessing each of these factors, including study design, study limitations (risk of bias), inconsistency, indirectness of study results, imprecision, and publication bias. It also specifies the quality of each primary outcome by categorizing studies into 4 levels (high, moderate, low, and very low).25 These criteria are listed in a supplemental Appendix (see Supplemental Digital Content 1, available at: http://links.lww.com/JCRP/A107).
A total of 9850 records were identified from the initial database search, 5752 records were excluded as duplicates, and 3994 records were excluded for various reasons on the basis of the titles and abstracts (reviews, letters, animal studies, or irrelevant to the analysis). The remaining 1 abstract and 103 full-text articles were assessed for eligibility and 95 studies were excluded. Finally, a total of 9 articles covering 403 patients with valid outcome data met the inclusion criteria. Figure 1 shows the PRISMA flow diagram of studies included in this review.
The study design and patient population of the included studies are described in Table 1. Three studies used a randomized study design (112 patients),26–28 3 studies used a nonrandomized controlled study design (76 patients),29–31 a pre- and post-intervention self-comparison study design was employed twice (70 patients),32,33 and a cohort with a control group design was used once (145 patients).34 Studies included both sexes and the mean age of the patients ranged from 23 to 48 yr. All studies analyzed in this review included ACHD. Table 2 summarizes exercise training and control group interventions in parallel group trials.
In 6 included controlled trials, the number of participants in the exercise group ranged from 4 to 31, with a median of 15.5. A home-based aerobic exercise program,26,27 individualized structured exercise program,28 comprehensive cardiac rehabilitation program,29 exercise program including bicycle ergometer training and weight training,30 and a resistance training program31 were conducted in exercise groups; the duration was from 30 d to 24 wk, with a median of 12 wk. The control group in 1 study was required to refrain from an exercise training protocol26; 2 studies allowed the controls to continue their usual level of physical activity.27,28 Two studies gave comprehensive education to the control groups29,30 and another study required nonexercising controls.31
Results of the risk-of-bias assessment of the included parallel group studies are presented in Table 3. All parallel group studies were free of other bias but showed a high risk for blinding of participants and personnel. Four of the studies26,27,29,30 reported the numbers and reasons for withdrawal or dropout. Three randomized controlled trials26–28 generated an adequately randomized sequence, but only 1 of them was conducted in a blinded fashion for the outcome assessment. The Newcastle Ottawa Scale case-control and cohort tools were used to assess the risk of bias of the case-controlled studies and the cohort study separately. All 3 observational studies32–34 were rated with a total score of >5, indicating a low risk of bias. Given that the number of trials pooled in the comparison included in this literature was quite small (maximum of 4 trials), no funnel plot analysis was performed.
Primary Outcome: Cardiorespiratory Fitness
Cardiorespiratory fitness was assessed using the criterion standard method of peak
O2 (mL/kg/min) measured by maximal oxygen uptake during a cardiopulmonary exercise test. Peak
O2 was assessed in 6 studies26–29,33,34 using cycle ergometry testing. Another study31 reported only change in peak
When data from 4 controlled studies were pooled (Figure 2, panel A),26–29 statistically significant higher peak
O2 was associated with exercise training in ACHD (MD = 3.22; 95% CI, 1.88-4.56; P < .00001). There was no evidence of heterogeneity (I2 = 0%).
Within observational studies (Figure 2, panel B), a statistically significant higher peak
O2 was also associated with exercise training in ACHD (MD = 1.96; 95% CI, 0.70-3.23; P = .002). There was evidence of moderate heterogeneity (I2 = 51%). Further exclusion of any single study did not materially alter the overall combined MD, with a range from 1.35 (95% CI, 0.30-2.39) to 2.43 (95% CI, 1.04-3.82). When only adjusted MDs were pooled in 2 observational studies, MD for peak
O2 was 0.77 (95% CI, −0.2 to 1.73; P = .12) and the heterogeneity of evidence was zero.
Primary Outcome: Maximal Exercise Workload
The impact of exercise training on maximal workload (watts) was assessed in detail in 3 controlled trials27,29,31 and 1 pre- and post-intervention study.33 Pooled analysis across these 4 studies showed a significant improvement in maximal workload in the exercise training group (MD = 11.46; 95% CI, 7.06-15.87; P < .00001). The heterogeneity of evidence was zero (I2 = 0%) (Figure 3).
Primary Outcome: Maximal Exercise Duration
When data from 2 controlled trials27,29 and 1 pre- and post-intervention comparison trial32 were pooled, a significant improvement in exercise duration was found in the exercise training group (MD = 2.04 min; 95% CI, 1.00-3.07; P = .0001; I2 = 0%) (Figure 4).
Secondary Outcome: Neurohumoral Activation
Four of the included trials (3 controlled trials26,27,30 and 1 pre- and post-intervention comparison trial33) reported NT-proBNP levels at baseline and after exercise training, but we failed to find a significant difference between groups on pooled analysis of studies reporting it (MD = 48.69 pg/L; 95% CI, −285.95 to 383.34; P = .78; I2 = 0%).
Secondary Outcome: RPE
Ratings of perceived exertion were measured by either the Borg 6-20 RPE scale27,33 or the revised 0-10 version30 in 3 of the included studies. Since the data were assessed by 2 different versions of the rating scale, it was not possible to merge all the data. Therefore, only pooled data from studies using the Borg 6-20 RPE scale27,33 were analyzed and no significant difference was found (MD =−0.00; 95% CI, −0.76 to 0.76; P = 1.00).
Secondary Outcome: Patient Safety
Exercise training was well tolerated among the participants in most included studies. In the pooled analysis, overall dropout rate from exercise training was 7.1% (due to undergoing pacemaker battery replacement, lack of time, no interest, moved away, or no reason stated). Furthermore, no major adverse events, such as progression of symptoms, heart failure, or death, were reported among the participants during the exercise training period of time.
The principal finding of this systematic review and meta-analysis of exercise training in individuals with ACHD is that exercise training is associated with a significant improvement in exercise capacity (Δ peak
O2, 1.96 mL/kg/min; Δ maximal workload, 11.46 watts; Δ maximal exercise duration, 2.04 min). Furthermore, exercise training was well tolerated by these patients, no significant improvement in neurohumoral activation and the RPE was reported. These findings suggest that exercise training could be used as a safe and effective adjunctive treatment for compensated stable ACHD.
The findings from this systematic review and meta-analysis have important clinical implications. Exercise training is recommended for patients with chronic cardiopulmonary conditions.35 Similarly, a recent review of ConHD recommended that patients with atrial septal defect, ventricular septal defect, patent ductus arteriosus, or other shunt ConHD can participate in any physical exercise if the condition is not combined with pulmonary hypertension, ventricular enlargement, or heart failure.36 However, many physicians have a conservative attitude toward participation in exercise by patients with ACHD but also have been skeptical about the safety of exercise training for the management of ACHD because of concerns about an increased incidence of sudden cardiac death during exercise.8 Contrary to these notions, our findings provide evidence for the efficacy and safety of exercise training in ACHD, especially for improving cardiorespiratory fitness.
Significant improvements were observed in cardiorespiratory fitness, measured as peak
O2, as the result of exercise training. A growing body of clinical and epidemiological evidence over the past 3 decades has firmly established that not only is cardiorespiratory fitness a potentially stronger predictor of mortality than established risk factors such as smoking, hypertension, high cholesterol, and type 2 diabetes mellitus, but that the addition of cardiorespiratory fitness to traditional risk factors significantly improves the classification of risk for adverse outcomes.37 A recent statement from the American Heart Association demonstrated that efforts to improve cardiorespiratory fitness should be a standard part of clinical encounters (eg, an accepted vital sign).10 In addition, Laukkanen et al38 suggested that a 1 mL/kg/min increase in peak
O2 was associated with a 9% reduction in relative risk for all-cause mortality (hazard ratio = 0.91; 95% CI, 0.87-0.95) and emphasized the importance of maintaining good cardiorespiratory fitness over the decades. One of the included studies29 showed a significant improvement in peak
O2 up to 4 mL/kg/min after 4-wk comprehensive cardiac rehabilitation program, which shows a clinically significant difference than that reported using comprehensive education program.
The underlying cause for the impaired aerobic exercise capacity in adults with ConHD is due to multiple factors, both cardiac and extracardiac,5 including reduced confidence in performing exercise training and impaired skeletal muscle function.3 Exercise training was proven to be beneficial for improving peripheral muscular function by enhancing endurance performance and strength in patients with ConHD, and this improvement was associated with increased oxygenation of peripheral muscles and faster recovery.39 Furthermore, we observed significant improvement in maximal exercise duration associated with exercise training, which had a strong inverse relation to overall mortality.38 Another finding from this review supports that exercise training can significantly increase peak exercise workload, which seems to be a valuable indicator of aerobic endurance capacity.40
However, changes in NT-proBNP levels were not statistically significant, which might be explained by the study by Matinez-Quintana et al30 that used a design including adults who not only had pulmonary hypertension but also left ventricular dysfunction associated with higher secondary NT pro-BNP levels, which involved a complex pathophysiology of the underlying cardiac anomaly. Moreover, no significant differences were found in the Borg RPE scale values when comparing exercise training with other treatments.
Low dropout rates, no exercise-associated adverse events, and no deaths were reported among the exercise training participants across all of the included studies (median 12 wk of exercise training, which indicated a relatively high degree of tolerance to exercise training in persons with ACHD). In other words, our findings suggested that appropriate exercise training can be considered as a safe strategy for the management of ACHD, which agrees with the findings of Chaix et al.8 Future studies are needed to determine whether these favorable effects of exercise training can predict a reduction in long-term adverse clinical events.
Although the New York Heart Association classifications of the exercise training participants with ACHD in the included studies ranged from class I to IV, some characteristics should be cautiously considered when recommending exercise training to ACHD. Noteworthy is that all the included studies used exercise training protocols that were properly supervised. Most of the exercise training protocols used lower workloads compared with current exercise recommendations for ConHD, and the exercise training was implemented only in medically stable patients with no recent change in the medication regimen.
There are several limitations to this study. First, there are only a limited number of clinical trials that have assessed the efficacy and safety of exercise training among ACHD, so that publication bias cannot be completely ruled out. Second, 3 of the 6 parallel group trials included in the pooled analysis were nonrandomized and 2 pre- and post-intervention studies and 1 cohort study were included, which highlights the heterogeneities of pooled analysis that was conducted in this study. Third, most of the included studies did not evaluate clinical meaningful events such as hospitalization and mortality end points. Fourth, statistical power was low to detect safety outcomes, which makes it relatively difficult to make general conclusions regarding the safety of exercise in groups with ACHD patients. Fifth, the quality of evidence (GRADE) for all outcome measurements was inconsistent and ranged from low to very low quality (see Supplemental Digital Content 2, available at: http://links.lww.com/JCRP/A108), which means that, in the future, data that are robust and have low risk of bias may change some of the results of the interventions assessed in this meta-analysis. Finally, most of the included studies were single center-based and had a relatively short follow-up period. Future multicenter, well-designed randomized controlled trials with longer duration of follow-up are needed.
Exercise training is relatively safe and associated with significant improvement in cardiorespiratory fitness among persons with ACHD. However, this analysis showed no difference between the experimental group and the control group for other outcomes. Nevertheless, interpretation of our results must be cautious considering the methodological drawbacks and poor data quality of the included trials. Future studies with longer duration of follow-up are needed to determine the best exercise training protocol to use to improve long-term clinical end points among these patients.
The authors thank Juping Liang for methodological assistance during the study. This study was supported by funding from Key Developing Disciplines Construction Program (Rehabilitation Medicine) of the Shanghai Municipal Commission of Health and Family Planning (#2015ZB0406); Program of Shanghai Municipal Health and Family Planning Commission (#201640067); and Early Life Plan of Shanghai Xinhua Hospital (#15QT17).
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