Background
Exercise training is a core component of cardiac rehabilitation (CR) [
1,
2] and has been associated with improvements of physical performance, body composition and quality of life, as well as blood pressure, glucose metabolism and lipid control [
1,
3,
4]. While the effects of multicomponent exercise-based CR on physical performance, body composition and quality of life are evident [
5‐
7], less is known about CR effects on insulin resistance and lipids in patients with CAD [
4], despite high prevalence of diabetes and dysmetabolism (54%) among patients enrolled in an early phase II CR [
8].
During the early stage of phase II CR, the standard care is focused mainly on clinical assessments of cardiac function and risk factors, and optimisation of pharmacological therapy [
9], while less emphasis is given on the initial implementation of progressive training programmes with optimal training loading due to the lack of exact training recommendation [
10], which would otherwise greatly improve the efficacy of CR efficacy. Therefore, previous studies in patients with CAD have applied only low-load (LL) to moderate-load RT [50–65% of one repetition maximum (1-RM)] in combination with moderate to high intensity AT and mostly showed no additional benefits on glucose metabolism and blood lipids when compared with control [
11,
12] and/or AT alone [
12,
13]. Whilst only the superior effects on maximal muscle strength were established following combined AT with high-load (HL) in our recent study [
14], such efficacy over combined AT with LL-RT or AT alone remains to be established on insulin resistance and lipids.
Since the recent recommendations for patients with CAD and coexisting diabetes advocates for the use of combined AT and RT at the highest intensity possible to achieve optimal control of glucose metabolism, dyslipidaemia and body composition in early phase of CR [
9], our study aimed to determine whether the dose-dependent relationship between RT load (LL-RT vs HL-RT) and improvements of glucose metabolism and lipids profile exists in patients with CAD.
Results
One hundred and fifty-four patients with CAD were screened for eligibility and 79 were included in the study (Fig.
1). During the study, 20 patients were lost to follow-up, mainly due to personal and medical reasons, and 59 patients were included in the final per-protocol analysis. On average, patients were 61 (8) (years old, had left ventricular ejection fraction 53(9) %), and were mostly males (75%) and non-smokers or ex-smokers (83%). In the AT group, more patients were diagnosed with atrial fibrillation than in the HL-RT and LL-RT groups (
p = 0.038). Otherwise, there no between-group differences in baseline anthropometry, clinical characteristics, smoking status and pharmacological therapy (Table
1). Following the training intervention, the dose of statins or ezetimibe significantly increased in all three training groups (AT: + 7 mg, p = 0.010; LL-RT: + 7 mg, p = 0.023; HL-RT: + 11 mg, p < 0.001), with no significant time x group interaction (Additional file
1: Table S1). There was also no difference between training groups in lipid lowering drug at baseline (p = 0.836) and post-training (p = 0.426) (Additional file
1: Table S2). Training adherence AT and RT was very high, only eight patients completed less than 36 AT sessions (one patient completed 35 sessions in AT group; one patient completed 34 sessions and four patients completed 35 sessions in LL-RT group; two patients completed 35 sessions in HL-RT group), and only one patient failed to complete all HL-RT sessions (35 completed sessions).
Table 1
Anthropometry, clinical characteristics and cardiovascular risk factors at baseline
Age (years) | 61 (8) | 61 (9) | 61 (7) | 62 (8) | 0.910 |
Sex [males, (%)] | 44 (75) | 14 (74) | 15 (79) | 15 (71) | 0.931 |
Anthropometry |
Height (cm) | 172.1 (8.4) | 170.4 (8.8) | 172.8 (8.6) | 172.9 (7.9) | 0.582 |
Weight (kg) | 85.47 (15.43) | 90.94 (19.04) | 81.46 (13.37) | 84.15 (12.56) | 0.148 |
Clinical data |
LVEF (%) | 53 (9) | 50 (45,60) | 55 (50, 60) | 50 (45,58) | 0.454 |
Time from clinical event to inclusion in CR (months) | 2.0 (1.5, 3.0) | 2.0 (2.0,2.5) | 2.5 (1.5, 3.0) | 2.0 (1.5, 2.8) | 0.832 |
Myocardial infarction, f (%) |
NSTEMI | 25 (42) | 9 (47) | 8 (42) | 8 (38) | 0.947 |
STEMI | 24 (41) | 7 (37) | 7 (37) | 10 (48) |
Unstable AP/PCI | 10 (17) | 3 (16) | 4 (21) | 3 (14) |
Comorbidities and risk factors, f (%) |
Arterial hypertension | 41 (70) | 15 (79) | 11 (58) | 15 (71) | 0.383 |
Hyperlipidemia | 49 (83) | 16 (84) | 14 (74) | 19 (91) | 0.384 |
Diabetes | 9 (15) | 4 (21) | 3 (16) | 2 (10) | 0.602 |
Atrial fibrillation | 5 (9) | 4 (21) | 1 (5) | 0 (0) | 0.038 |
Thyroid disease | 5 (9) | 2 (11) | 2 (11) | 1 (5) | 0.727 |
Renal disease | 4 (7) | 0 (0) | 2 (11) | 2 (10) | 0.534 |
Smoking, f (%) |
Non-smoker | 14 (24) | 3 (16) | 3 (16) | 8 (38) | 0.346 |
Ex-smoker | 35 (59) | 13 (68) | 11 (58) | 11 (52) |
Current smoker | 10 (17) | 3 (16) | 5 (26) | 2 (10) |
Pharmacological therapy, f (%) |
ASA | 57 (97) | 17 (90) | 19 (100) | 21 (100) | 0.200 |
Beta blocker | 59 (100) | 19 (100) | 19 (100) | 21 (100) | 1.000 |
ACE inhibitor/ARB | 58 (98) | 19 (100) | 18 (95) | 21 (100) | 0.644 |
Statin/Ezetimibe | 59 (100) | 19 (100) | 19 (100) | 21 (100) | 1.000 |
Antiplatelets | 58 (98) | 18 (95) | 19 (100) | 21 (100) | 0.644 |
Anticoagulation | 5 (9) | 3 (16) | 1 (5) | 1 (5) | 0.509 |
Diuretic | 5 (9) | 4 (21) | 0 (0) | 1 (5) | 0.071 |
With exception of significant difference between groups in baseline triglycerides (p = 0.014), training groups did not differ in baseline glucose and insulin levels, HOMA2-IR and other blood lipids (Table
2). After adjusting for baseline difference, there was no significant difference between groups in post-training triglycerides levels (p = 0.927). Two-way ANOVA has shown a significant effect of time on total cholesterol and LDL (both p < 0.001), but no effects of time x group interaction on glucose levels, insulin levels, HOMA2-IR and blood lipids (all interaction p > 0.326). When compared with baseline, total cholesterol and LDL were significantly lower following AT [total cholesterol: − 0.4 mmol/l (− 0.7 mmol/l, − 0.1 mmol/l), p = 0.013; LDL: − 0.4 mmol/l (-0.7 mmol/l, − 0.1 mmol/l), p = 0.006] and HL-RT [total cholesterol: − 0.5 mmol/l (− 0.8 mmol/l, − 0.2 mmol/l), p = 0.002; LDL: − 0.5 mol/l (− 0.7 mmol/l, − 0.2 mmol/l), p = 0.002].
Table 2
Baseline and post training levels of glucose, insulin resistance and blood lipids
Glucose (mmol/l) | AT | 15 | 6.0 (1.2) | 6.1 (1.4) | p = 0.741 η2 = 0.002 | p = 0.791 η2 = 0.010 |
LL-RT | 16 | 5.6 (0.6) | 5.5 (0.7) |
HL-RT | 19 | 5.6 (0.5) | 5.7 (0.5) |
Insulin (pmol/l) | AT | 15 | 95 (46) | 98 (58) | p = 0.923 η2 = 0.000 | p = 0.885 η2 = 0.005 |
LL-RT | 16 | 78 (38) | 77 (31) |
HL-RT | 19 | 74 (56) | 70 (44) |
HOMA2-IR (units) | AT | 15 | 1.82 (0.86) | 1.90 (1.12) | p = 0.965 η2 = 0.000 | p = 0.880 η2 = 0.005 |
LL-RT | 16 | 1.49 (0.71) | 1.46 (0.58) |
HL-RT | 19 | 1.40 (1.05) | 1.34 (0.82) |
Total cholesterol (mmol/l) | AT | 19 | 3.8 (1.1) | 3.4 (0.9) | p < 0.001 η2 = 0.013 | p = 0.492 η2 = 0.025 |
LL-RT | 19 | 3.2 (0.7) | 3.0 (0.5) |
HL-RT | 21 | 3.6 (0.9) | 3.2 (0.5) |
HDL (mmol/l) | AT | 19 | 1.2 (0.5) | 1.3 (0.4) | p = 0.961 η2 = 0.000 | p = 0.573 η2 = 0.020 |
LL-RT | 19 | 1.2 (0.4) | 1.2 (0.3) |
HL-RT | 21 | 1.2 (0.3) | 1.2 (0.3) |
LDL (mmol/l) | AT | 19 | 2.0 (1.0) | 1.6 (0.7) | p < 0.001 η2 = 0.260 | p = 0.499 η2 = 0.025 |
LL-RT | 19 | 1.6 (0.5) | 1.4 (0.4) |
HL-RT | 21 | 2.0 (0.7) | 1.5 (0.4) |
Triglycerides (mmol/l) | AT | 19 | 1.8 (1.0) | 1.7 (0.9) | p < 0.001 η2 = 0.649 | p = 0.927 η2 = 0.003 |
LL-RT | 19 | 1.3 (0.4) | 1.3 (0.5) |
HL-RT | 21 | 1.3 (0.4) | 1.2 (0.4) |
Table
3 presents the change of body mass, lean mass and fat mass following training intervention in all groups. Training groups significantly differed in baseline fat mass (LL-RT vs AT = − 8.20 kg, p = 0.035). After adjusting for baseline difference, there was no significant differences between groups in post-training fat mass. Two-way repeated measures ANOVA has shown a significant time effect for lean mass, but no effects of time x group interaction on any of the body composition variables. When compared with baseline, AT group significantly increased fat % [mean difference (95% Confidence interval for mean difference), + 1% (0%, + 2%), p = 0.048], decreased lean mass % [− 1% (0%, − 2%), p = 0.048] and lean mass [− 1.05 kg (− 1.89 kg, − 0.20 kg), p = 0.016] following the training intervention. Similarly, HL-RT group significantly decreased lean mass [− 1.05 kg (− 1.87 kg, − 0.22 kg), p = 0.014].
Table 3
Baseline and post-training body composition
Body mass (kg) | AT | 19 | 90.94 (19.04) | 90.49 (17.87) | p = 0.187 η2 = 0.031 | p = 0.974 η2 = 0.001 |
LL-RT | 19 | 81.46 (13.37) | 80.91 (13.90) |
HL-RT | 21 | 84.15 (12.56) | 83.47 (13.48) |
Fat (%) | AT | 19 | 28.2 (9.2) | 29.2 (8.7) | p = 0.500 η2 = 0.008 | p = 0.138 η2 = 0.070 |
LL-RT | 19 | 22.3 (4.7) | 22.0 (5.2) |
HL-RT | 20 | 24.9 (8.4) | 24.7 (7.6) |
Fat (kg) | AT | 19 | 26.0 (11.0) | 26.7 (10.3) | p < 0.001 η2 = 0.900 | p = 0.095 η2 = 0.083 |
LL-RT | 19 | 17.8 (3.3) | 17.6 (4.5) |
HL-RT | 20 | 21.0 (8.3) | 20.5 (7.5) |
Lean (%) | AT | 19 | 71.8 (9.2) | 70.8 (8.7) | p = 0.497 η2 = 0.008 | p = 0.139 η2 = 0.069 |
LL-RT | 19 | 77.7 (4.7) | 78.0 (5.2) |
HL-RT | 20 | 75.1 (8.4) | 75.3 (7.6) |
Lean (kg) | AT | 19 | 64.9 (13.6) | 63.9 (13.1) | p = 0.002 η2 = 0.166 | p = 0.354 η2 = 0.037 |
LL-RT | 19 | 63.6 (12.5) | 63.3 (12.4) |
HL-RT | 20 | 63.4 (11.7) | 62.4 (11.5) |
Additional exploratory analysis of associations between post-training difference in blood markers and post-training difference body composition revealed no significant correlation when calculated on a whole sample and in patient subgroups with and without diabetes (Table
4). In absence of significant time x group interaction, additional comparison between baseline and post-training levels of glucose and insulin metabolism also showed no improvement in patients with (p = 0.220–0.910) and without diabetes (p = 0.713–0.953) (Table
5). In addition, the exploratory analysis of associations between post-training difference in glucose levels and post-training difference in statin dose showed only significant positive correlation following HL-RT (Spearman`s correlation coefficient = 0.471, p = 0.049) (Additional file
1: Table S3).
Table 4
Correlations between post-training difference in body composition and blood markers
Non-diabetic (n = 49) | Fat mass difference | Spearman rho | − 0.006 | 0.067 | − 0.016 | 0.071 | 0.046 | 0.032 | 0.000 |
p | 0.969 | 0.645 | 0.915 | 0.630 | 0.752 | 0.825 | 1.000 |
Lean mass difference | Spearman rho | 0.007 | − 0.063 | 0.017 | − 0.076 | − 0.048 | − 0.039 | − 0.005 |
p | 0.963 | 0.666 | 0.908 | 0.603 | 0.744 | 0.793 | 0.973 |
Diabetic (n = 9) | Fat mass difference | Spearman rho | − 0.233 | 0.250 | − 0.133 | 0.008 | − 0.420 | − 0.043 | 0.417 |
p | 0.546 | 0.516 | 0.732 | 0.983 | 0.260 | 0.913 | 0.265 |
Lean mass difference | Spearman rho | 0.233 | − 0.250 | 0.133 | − 0.008 | 0.420 | 0.043 | − 0.417 |
p | 0.546 | 0.516 | 0.732 | 0.983 | 0.260 | 0.913 | 0.265 |
Sample (n = 58) | Fat mass difference | Spearman rho | − 0.022 | 0.149 | − 0.016 | − 0.006 | − 0.038 | − 0.046 | 0.090 |
p | 0.868 | 0.264 | 0.903 | 0.965 | 0.775 | 0.733 | 0.503 |
Lean mass difference | Spearman rho | 0.025 | − 0.146 | 0.019 | 0.002 | 0.037 | 0.041 | − 0.092 |
p | 0.855 | 0.275 | 0.888 | 0.988 | 0.780 | 0.758 | 0.491 |
Table 5
Baseline and post-training glucose and insulin metabolism in coronary disease patients with and without diabetes
Non-diabetic patients | Glucose (mmol/l) | 5.7 (0.8) | 5.7. (0.9) | − 0.370 | 0.713 |
Insulin (pmol/l) | 69 (48, 116) | 73 (47, 111) | − 0.065 | 0.953 |
HOMA2-IR (unit) | 1.34 (0.93, 2.19) | 1.34 (0.89, 2.13) | − 0.121 | 0.909 |
Diabetic patients | Glucose (mmol/l) | 8.6 (3.8) | 7.2 (2.0) | 1.330 | 0.220 |
Insulin (pmol/l) | 101 (80, 173) | 111 (76, 461) | − 0.533 | 0.652 |
HOMA2-IR (unit) | 2.00 (1.70, 4.25) | 2.38 (1.46, 8.09) | − 0.178 | 0.910 |
Discussion
This study is one of the first to compare the dose-dependent relationship between RT load and improvements in insulin resistance and lipids profile in patients with CAD enrolled in early phase II CR. The addition of RT to AT, regardless of the RT load showed no additional benefits on insulin resistance and lipids. However, HL-RT and AT decreased total cholesterol and LDL following training intervention, whereas there were no differences between training modalities in body composition or blood biomarkers. In addition, there was also no relationship between post-training difference in body composition and post-training difference in blood markers in patients with CAD.
The levels of insulin resistance were not improved with the addition of RT to AT, likely due to lower HOMA2-IR values than are cut-off values for determining potential metabolic risk in nondiabetic individuals (HOMA2-IR > 1.8) [
26]. This contrasts with previous studies, which mostly included patients with obesity, the metabolic syndrome and diabetes with worse metabolic and body composition status (e.g., higher body fat % and body mass index) in comparison to our sample of patients with CAD [
27‐
32]. Moreover, fewer multiple exercise interventions were performed in patients with CAD [
11‐
13,
33,
34]. After exercise-based CR, studies showed no difference between combined AT and RT, and AT, RT or usual care alone in glucose, insulin resistance and/or blood lipids, similarly, as observed in our study. Most interventions with longer training duration (> 8 weeks), regardless of training modality (AT, RT or combined AT and RT), improved insulin resistance and blood lipids levels [
33,
34], which partially corroborates with benefits observed following AT and HL-RT in our study. Otherwise, shorter training intervention (< 6 weeks) failed to elicit any between-group or within groups improvements [
12,
13], despite using similar RT loads as longer training interventions (60%-65% of 1-RM). In our study, the use of only single lower limb resistance exercise likely elicited suboptimal stimulus for any additional cardiometabolic benefits.
With a high prevalence of co-exiting diabetes in patients with CAD [
8], our findings can be compared with similar interventions in patients with metabolic syndrome, prediabetes or diabetes. The studies that enrolled similarly aged patients with metabolic syndrome have demonstrated absence of between-group difference and only post-training improvements in insulin resistance and/or blood lipids following each training modality [
27,
28]. On contrary, one study has shown superiority of combined RT and AT over AT alone on insulin resistance in middle-aged obese individuals [
30]. When compared with our findings, the authors measured insulin resistance only 12 h after the last training session, which may in combination with more metabolically demanding protocols of AT (weekly exergy expenditure of 14 kcal/kg of body weight) and HL-RT (multiple whole body resistance exercises) explain the discrepancy between studies. In addition, the worse metabolic clinical status of the participants cannot be ruled out [
30], as our patients entered the CR with optimized drug therapy and with lower prevalence of diabetes as expected, thus, the improvement in insulin resistance was harder to achieve, regardless of the training modality. Furthermore, our findings are also in line with a recent meta-analysis of patients with type II diabetes that showed similar effects of LL-RT and HL-RT when compared with AT on glycated hemoglobin, insulin levels and insulin resistance [
32]. In contrast to our findings, the analysis even showed a superior effects of HL-RT over usual care in reduction of fasting glucose (− 0.92 mmol/l). In addition, LL-RT was associated with a greater decrease in insulin levels than HL-RT when compared to usual care [
32], which suggests that gains in muscle endurance may play a superior role over maximal muscle strength gains in improvement of insulin metabolism. However, direct comparison with our study cannot be made due to only indirect comparison between HL-RT and LL-RT in the meta-analysis [
32] and due to lower prevalence of diabetes in our study (15%). The effects of dose-dependent relationship between RT load and improvement in insulin resistance also remains to be established in similarly aged older adults without type II diabetes, whereas previous interventions have only combined LL- to moderate load-RT with AT and have showed an improvement in insulin resistance over AT alone [
35,
36].
The effect of combined AT and RT on body mass differed among previous studies in patients with CAD [
21,
33,
37,
38], with two similarly designed studies supporting our findings [
21,
37]. Most previous interventional studies showed decreased fat mass and/or fat % following combined AT and RT [
33], which was superior to AT alone [
21,
37‐
39]. In contrast, we have demonstrated an increase in fat % following AT, and maintained fat % following both LL-RT and HL-RT. Our results can be partially explained by an increased energy demands when participating in RT, as similarly increased metabolism after RT was observed in healthy older adults (up to 15% of total daily energy expenditure) [
40]. Furthermore, muscle hypertrophy was evident following most combined AT and RT interventions in patients with CAD [
21,
37‐
39], with greater stimulus achieved following moderate-to HL-RT [
21] or HL-RT [
38] and after longer intervention (> 24 weeks) [
21,
37]. Since most of the previous studies applied multiple RT exercises for upper and lower extremities [
21,
37,
38], it seems that using only one lower extremity RT exercise may have provided inadequate stimulus to promote superior effects on lean body mass when compared with solely AT. In addition, the discrepancies between the findings can also be attributed to type of measure, as most of the previous studies measured body composition with Dual-energy X-ray absorptiometry, which is more accurate than bioimpedance [
41] used in our study.
Our findings, although novel, need to be interpreted with regards to following limitations. Firstly, our study was primarily powered only for primary study outcomes (maximal aerobic capacity and maximal voluntary contraction) [
14], therefore all secondary outcomes of this study must be interpreted as exploratory, especially HOMA2-IR. Nevertheless, our sample size was comparable to some of the previous studies in patients with CAD [
13,
33]. Secondly, coronavirus-19 pandemic restriction prevented blinding of the outcome assessors. In addition, the staff relocations to other departments also limited the inclusion of more than one lower limb exercise (e.g., leg press) in RT, which may elicit greater changes in body composition, and glucose and lipids metabolism, and consequently distinguished the effects between training interventions. Thirdly, the prevalence of diabetes was low in our sample (15%) compared with recent EUROASPIRE IV survey cohort [
8], therefore, our results cannot be directly translated in CAD patients and predominately co-exiting diabetes. Future multimodal training intervention should therefore include more CAD patients with metabolic syndrome or with diabetes. Lastly, higher doses of lipid lowering drugs were likely superior over exercise training effects.
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