Regular physical exercise is an established therapeutic strategy with prognostic benefits in cardiovascular disease (CVD). It improves exercise capacity and quality of life and attenuates disease progression.1–5 Traditionally, exercise prescription has involved ≥30 min of endurance exercise for ≥4 d/wk at heart rates (HRs) reflecting an intensity of 50-60% of peak
O2.6 Recent studies have observed that high-intensity interval training (HIIT), in which patients exercise at intensities up to 100% of peak HR,7 may be at least as effective as moderate-intensity continuous exercise (MICE; 60%-80% of peak HR) in patients with CVD.5,6,8 Resistance training (RT) has also been observed to have positive effects on health, especially muscle strength and quality of life.9 Although traditional exercise prescriptions have remained largely unchanged, current guidelines emphasize the importance of exercise training for secondary prevention and cautiously include HIIT and RT for most patients with CVD.10 However, HIIT and RT may not be appropriate for all patients with CVD or in community-based settings because of the potential increase in risk of adverse events.11,12 Moderate-intensity interval training (MIIT) has been suggested to be a viable and safe alternative to HIIT that may be effective in nonclinical settings such as a cardiac maintenance program (CMP).13–17 MIIT protocols are more attractive to certain individuals than HIIT or MICE.18
Diabetes mellitus (DM) and coronary artery disease (CAD) are 2 of the primary CVD, which lead to more advanced heart disease, including heart failure.19–21 Two-thirds of deaths in people with DM are from CVD. Reducing atherosclerotic CVD is a common challenge among both populations.
Although improvements in health and fitness have been observed in studies on MIIT and RT, translational studies examining these methods in less controlled community settings are lacking. Therefore, the purpose of this study was to examine the feasibility and effectiveness of MIIT with RT on increasing cardiopulmonary fitness in patients with CAD and/or DM in a community-based CMP.
PATIENTS AND METHODS
Participants from 18-80 yr of age insured with Techniker Krankenkasse Health Insurance Company (TK) in Munich, Germany, and living in the greater Munich area were eligible. Patients were screened by chart review and recruited by telephone interview. Eligible participants were diagnosed with CAD and/or DM according to International Statistical Classification of Diseases and Related Health Problems codes. CAD was confirmed if the patient had prior coronary angiography showing at least 1-vessel disease. DM was confirmed through positive blood tests for fasting blood sugar (≥126 mg/dL [≥7 mmol/L]), HbA1c level of 6.5% or higher or current antidiabetic drug medication.22 Patients with CAD and DM were targeted as the 2 populations with CVD, who would profit the most through long-term exercise-based CMP.
This study was conducted using a 1-arm prospective, repeated-measures per-protocol design performed in collaboration with TK. Participants received an individualized endurance exercise prescription at baseline based on cardiopulmonary exercise test (CPX) results. They also performed regular resistance exercise as tolerated. Although the focus of this study was on clinical and exercise performance metrics, 2 structured 90-min sessions were offered to patients focusing on motivational issues according to the MoVo concept described previously.23
The study protocol was approved by the ethics committee of the Technical University of Munich (#5132/11) and the TK. Trial endpoints were evaluated at baseline and at 6 mo. Patients were excluded if they were currently active in a rehabilitation or other regular structured physical activity, were clinically unstable (eg, uncontrolled hypertension or blood glucose), or were unable or unwilling to understand or comply with trial procedures. Baseline assessment consisted of a clinical examination, laboratory parameters, and CPX.
Supervised exercise sessions were performed in 10 different rehabilitation centers in the greater Munich area. Therapists were instructed and monitored by the study core center. The exercise prescription included two 6-wk phases followed by one 12-wk phase with reduced supervision and higher exercise intensity as participants progressed through the program (Figures 1 and 2). Patients performed warm-up and cooldown for 5-10 min before and after exercise at exercise intensities between 7 and 11 (very, very light to fairly light) on the 6 to 20 Borg ratings of perceived exertion scale (Borg RPE Scale, Borg Perception). During supervised exercise, these phases were monitored by trainers who were instructed to intervene if patients seemed to be exercising at inappropriate (too high or too low) intensities. Patients were instructed how to enter exercises into their individual training diaries for center-based and home-based training correctly. Therapists were also trained and instructed to frequently discuss the training diaries and issues on progress, motivation, or any problems in maintaining home-based training and physical activity with the patients. If needed, training adaption or advice for home-based training were provided and evaluated at the next center-based exercise session.
ENDURANCE EXERCISE PRESCRIPTION
Endurance exercise was performed on the basis of the HRs calculated using HR at peak
O2 during CPX. Endurance exercise intensity was recorded and assessed using HR and the Borg RPE scale and was prescribed to be between 11 (fairly light) and 13 (somewhat hard).24 MIIT was performed for a duration of 27-33 min/session and MICE was performed for 30-40 min/session. As illustrated in Figure 2, the ratio of high- to low-intensity exercise during MIIT was progressively increased throughout the trial.
RESISTANCE EXERCISE PRESCRIPTION
Resistance exercise intensity was recorded and assessed using the Borg RPE scale and was designed to be between 11 (fairly light) and 13 (somewhat hard).24 The resistance exercise protocol included the following large muscle exercises: chest press (pectoral), lat pulldown (latissimus dorsi), seated row (rhomboids), and leg press (quadriceps). RT exercises were regularly performed at a frequency of 15-20 repetitions for 2-3 sets. If the participant was not able to perform any of the RT exercises, an alternative but equivalent exercise was selected. Additional RT exercise was prescribed by the rehabilitation team according to the personal needs of the patient. RT was performed on machines, cable motion stations, dumbbells, and/or stretch bands. Exercise sessions were performed in small groups of up to 5 participants. The resistance exercise component added approximately 20 min to each center-based exercise session. The volume and intensity of resistance exercises were increased as needed to achieve target RPE intensities. Patients were encouraged to perform adapted resistance exercise at home (eg, using stretch bands) but these were not specifically prescribed.
Cardiorespiratory fitness was assessed using a 3-min stepwise stage CPX on cycle ergometers (Lode, Excalibur Sport), starting with 25W and increasing 25W every stage. Participants exercised to volitional exhaustion under the supervision of a physician and trained study nurses, who were instructed to terminate testing based on conventional published guidelines.25 Respiratory gases were recorded breath-by-breath and the electrocardiogram data were recorded continuously (CORTEX, Biophysik). At rest and at the end of each 3-min stage, ratings of perceived exertion were recorded manually using the Borg RPE Scale.24 Peak respiratory exchange ratio (
O2) >1.05, peak perceived exertion >16, and inability to continue were considered primary exhaustion criteria. Maximal workload was defined as the highest load reached during exercise testing. Peak
O2 and peak respiratory exchange ratio were determined by 2 investigators independently according to current guidelines.25,26 Submaximal exercise performance was measured at the first ventilatory threshold, calculated using the V-slope method and verified visually by 2 independent investigators.27
Blood was sampled from the antecubital vein after a minimum of 8 hr fasting. Blood was centrifuged and sent to a central commercial laboratory (Synlab Labor, Munich, Germany) within 4 hr. The following variables were measured: glycated hemoglobin (HbA1c), HOMA score (the quotient of basal insulin and basal glucose levels) for blood glucose homeostasis, HDL and LDL cholesterol, triglycerides, high-sensitivity C-reactive protein (hs-CRP), and adiponectin.
The following anthropometric data were measured at baseline: weight and height using standard instruments. Percent body fat was measured using the 7-site skinfold method.28 Abdominal girth was measured in centimeters at the level of the navel.
All participants who presented at follow-up were considered program completers and included in the data analysis (per-protocol analysis). Parametric quantitative data are described by mean ± SD. Qualitative data are presented as absolute and relative frequencies. For nonparametric data, median and interquartile ranges (IQR) are presented. For calculating within-group treatment differences, the Student t tests for dependent samples were used.
To address dose-response, patients who performed more than 70% of training sessions were compared with those who did not, using the Student t test for independent samples. All statistical tests were performed as 2-sided tests using a significance level of 5%. For relevant effect measures, 95% CI are presented. All analyses were performed with SPSS v23 (IBM).
RECRUITMENT AND SAMPLE SIZE
After 1522 individuals were contacted by telephone interview, 476 (31%) patients presented for baseline screening evaluation. Of these, 85 patients did not start the program because of various reasons (eg, time issues, distance to training center, and orthopedic issues).
From the 391 patients who initiated the trial, 99 patients (24%) dropped out and reasons are summarized in Table 1. Six patients died after baseline assessments but before completing the trial (Figure 3).
Baseline characteristics of patients (completers vs dropouts) are reported in Table 2. Completers were significantly older. Weight difference was not significant after correction for BMI.
As expected, HbA1c in the entire population including persons without DM did not significantly improve, but it showed significant improvement in patients with known DM. The HOMA score improved significantly in the entire sample. Improvements in LDL cholesterol are likely due to adjustments made to medication dosing at baseline when the cholesterol level was too high. HDL cholesterol showed no improvement. Patients with insulin-dependent DM (n = 38) reduced daily injected insulin dosage from 42 to 26 IU (95% CI, −24.327 to −7.541; P < .001) while HbA1c remained constant (7.38 ± 1.14% vs 7.29 ± 1.60%; P = .60). Of the patients who completed the baseline and follow-up assessments, 211 (72.3%) participated in >70% of training sessions. These patients increased peak
O2 more than those who participated in <70% (21.7 ± 6.0 to 23.3 ± 6.3 mL/kg/min; 95% CI, −2.2 to −1.1; P < .001). hs-CRP, HbA1c, triglycerides, and HOMA score also improved significantly more in this group of “adherent” participants compared with the “nonadherent.” Adiponectin and HDL cholesterol remained unchanged (Table 3).
When dividing the patient cohort into 2 groups (DM vs CAD without DM), the improvements in peak VO2, as well as maximal and submaximal workload remained significant, although patients without DM tended to be slightly fitter (peak
O2 improved from 23.1 ± 6.0 to 23.9 ± 6.0 mL/kg/min in patients without DM compared with patients with DM who improved from 21.1 ± 6.1 to 22.1 ± 6.3 mL/kg/min [both P < .05]) (Table 4).
Our study adds 2 major contributions to the field of CAD and DM exercise rehabilitation programming. First, we were successful in prospectively applying MIIT in a population-based experimental CMP. Second, we have shown that a combination of MIIT and RT resulted in significant increases in maximal and submaximal exercise performance, improved blood sugar control, and reduced chronic inflammation.
Prognostic benefits of exercise training in patients with CAD are well established. In a meta-analysis, Taylor and colleagues1 observed that exercise-based cardiac rehabilitation was associated with a significant decrease in cardiac mortality (26%) and all-cause mortality (20%). The participation in long-term CMPs has also been suggested to improve physical exercise performance, physical activity levels, and health-related quality of life, especially when integrating combined exercise.29,30 Higher intensities such as those in HIIT have been observed to be superior in improving exercise performance in several small studies, although these data have yet to be replicated in a larger cohorts.5,31 In addition, the data on safety of HIIT remain equivocal32; the only study to address feasibility of HIIT in a rehabilitation setting reported an event rate of only 1/170 000 training hr in >4000 patients at a single rehabilitation center. However, this rate was double that of MICE.32,33 The high prevalence of a sedentary lifestyle in those patients eligible for rehabilitation and the recent popularity of interval training has highlighted the need for an alternative to both MICE and HIIT.34,35 MIIT, which incorporates interval training at lower intensities than traditional HIIT, may have the potential to introduce sedentary individuals to exercise in a way that is both safe and attractive.13 Furthermore, although it is still not well investigated, despite a similar energy expenditure and intensity, intermittent and continuous exercises have been observed to result in different physiological responses. The intermittent modality seems to lead to a larger recruitment of fast-twitch fibers and induces greater metabolic variations, which would tend to favor mitochondrial development.36
Our study builds on previous studies of exercise performance in CAD and DM.5,13,37 We have demonstrated that MICE, MIIT, and RT prescriptions can be translated effectively into community-based settings over a long duration. This was accomplished with comparable dropout rates to previous trials, significant improvement of exercise capacity, and improved control of blood sugar and inflammation. One common critique of exercise interventions in which continuous and interval endurance exercise are compared is the lack of control over the energy expenditure (EE) between protocols. Without directly measuring EE (eg, indirect calorimetry) during exercise, it is extremely difficult to accurately control for this variable. In fact, a recent meta-analysis concluded that there is uncertainty and variation in actual training intensities compared to program targets in 13 studies, which compared endurance exercise using different intensities.38
A total of 1522 patients were reached by telephone interview. Of these, only 26% volunteered to participate in the program and, of those, 72 patients were lost to follow-up because of a lack of motivation or distance to the exercise sessions. Although this appears to be representative of contemporary studies,39 further investigation is needed to understand limited interest in participating in secondary preventative programs for patients with CAD and DM. Efforts also should be made toward aiding patients to complete rehabilitation programs, such as the feasibility of telemedicine, which may increase enrollment and participation and reduce dropouts due to distance to the training center.40 Including regular contact between the therapists and patients would also likely increase motivation to participate in regular exercise. However, limitation of resources within a community setting needs to be taken into account. Emerging technologies, such as wearables and mobile health platforms, have the potential to support an improvement in exercise participation through continuous updating of personalized rehabilitation plans by regular digital contact.41
To better represent a community-based program and the reproducibility of our results, 10 different nonclinical rehabilitation centers were chosen to participate rather than highly specialized university hospitals. One advantage of using outpatient exercise facilities is that the participants receive direct feedback from therapists for ongoing modification to the exercise program as needed and maintaining a high level of motivation. However, outpatient centers also face challenges. For implementation of this lifestyle program into routine treatment of cardiac patients, detailed quality manuals need to be created to ensure optimal care by medical staff as well as by staff at rehabilitation centers. Furthermore, financial support must be provided to ensure the long-term durability of such programs. The collaboration of insurers with physicians and therapists seen in this study is one way to achieve these goals. Cost-effectiveness, however, must be evaluated in a long-term follow-up study.
The results of this study must be interpreted within the context of the following limitations. Primarily, our study was not designed as a randomized controlled trial and did not include a control group. Furthermore, we did not conduct a primary intention-to-treat analysis (ie, patients who dropped out were not included in the analyses). As we did not control recruitment and could not clinically assess participants who dropped out, an intention-to-treat design would have resulted in a large amount of inferring for missing data and hampered our ability to address our primary research question. However, the fact that no medical illnesses were identified as a cause of dropping out during comprehensive follow-up, provides a degree a reassurance in our results. Although we did not control for changes/adjustments in medication, this was 1 of the positive outcomes of the study; most patients were able to reduce medication usage (especially DM medication). Finally, all patients with known CAD or DM were included; only those who were unable to exercise were excluded. The heterogeneous sample and lack of control allowed us to observe the experiment in a “real-life” setting without the constraints of homogeneity and crossover, which occur in randomized controlled trials. However, a trial done with such a design may add to the results of this study.
A combination of home- and center-based MICE, MIIT, and RT seems to be safe and effective for patients with CAD and/or DM in a 6-mo CMP; resulting in increased submaximal and maximal exercise performance and improvements in control of blood sugar and inflammation.
The authors thank the competent therapists at Therapie Punkt Ostbahnh of, Olching, Haar, Vaterstetten, Grafing, Schwabing. Schwabinger Reha-GmbH, Giesinger Reha-GmbH, PAT-Implerstrasse and Reha Neuperlach Süd. This study was made possible through funding from Techniker Krankenkasse Health Insurance Company.
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