Anabolic and Inflammatory Response to High- and Low-Load Resistance Training in Patients with Coronary Artery Disease: A Randomized Controlled Trial

Resistance training (RT) is increasingly used in cardiac rehabilitation along with standard aerobic training (AT) as a tool to address sarcopenia and frailty in patients with coronary artery disease (CAD) and as an intervention associated with reduced all-cause mortality and cardiovascular risk factors.1 Combining RT and AT induces greater benefits in terms of improved aerobic capacity, muscle strength, and body composition as compared with AT alone.1 The effects of combining RT and AT on anabolic and inflammatory response, however, remain unknown. Only a few studies have examined the effects of either AT or RT alone or combined AT and RT on inflammation in patients with CAD or heart failure,2–5 and none investigated the effects of exercise training on growth factors, despite clear associations between reduced levels of growth hormone and insulin-like growth factor 1 (IGF-1) with a higher prevalence of CAD and cardiovascular risk.6 Previous training interventions combined only progressive low-load (LL) to moderate-load RT with interval AT,2–5,7 whereas the effects of high-load (HL) RT remain to be explored. The latter is particularly interesting, as we have recently demonstrated superior effects of HL-RT over LL-RT in improvement of maximal muscle strength in patients with CAD.8 This could also induce greater anabolic and anti-inflammatory benefits; therefore, the current analysis explored the effects of combined LL-RT or HL-RT with AT in comparison with AT on anabolism and inflammation in patients with CAD. METHODS Stable patients with CAD (acute coronary syndrome and/or percutaneous coronary intervention) with left ventricular ejection fraction ≥40% were recruited and completed the baseline cardiopulmonary exercise test.9 After baseline assessments, patients were cluster randomized (3:3:3-5:5:5 patients/cluster) to AT (40 min of interval cycling; intervals of 3-5 min of workload cycling at the intensity of 50-80% of baseline maximum power output separated by 2 min of rest), combined AT and LL-RT (three sets, 12-22 repetitions/set at 35-40% of one repetition maximum [1-RM]), or combined AT and HL-RT (three sets, 6-11 repetitions/set at 70-80% of 1-RM). Training within an outpatient cardiac rehabilitation program was performed three times/wk, with 48-72 hr of rest between sessions over 12 wk or until completing 36 sessions. Additional information regarding the study design and protocols along with safety considerations is available elsewhere.9 An adjusted ramp protocol was performed on an ERG 911 ergometer (Schiller) to assess maximal aerobic capacity. After spirometry and obtained baseline heart rate, blood pressure, and gas exchange values, the intensity was increased for 10-25 W/min until the onset of fatigue and/or other contraindications.9 Both 1-RM testing and RT were performed using a Leg Press Pro 2 (Life Fitness). The 1-RM was collected using the progressive submaximal strength test, wherein the weight was increased until reaching the workload that could be lifted three to five times (3-5 RM). The 1-RM was calculated using the equation (predicted 1-RM = maximal load lifted/1.0278 − 0.0278 × number of repetitions).10 Blood samples were collected in the morning after overnight fasting (≥10 hr) prior to the first and last training sessions. Serum was prepared with a 10-min centrifugation at 1467 g and 20°C, aliquoted into 1.8-mL cryovials, and stored ≤ −70°C until further analysis. Concentrations of IGF-1 and growth hormone were measured using a classic sandwich enzyme-linked immunosorbent assay, and C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), and vascular endothelial growth factor were determined using xMAP technology on a MagPix analyzer (R&D Systems, USA). The selection of inflammatory (TNF-α, CRP), endothelial (vascular endothelial growth factor), and anabolic blood biomarkers (growth hormone, IGF-1) that are associated with the progression of CAD and heart failure was based on the previous training intervention in cardiac rehabilitation.5,7 This report is a pre-specified secondary outcomes analysis of a randomized controlled trial.8,9 Descriptive variables are presented as n (%), and numerical variables are presented as mean ± SD. Baseline between-group differences were assessed using one-way analysis of variance for normally distributed variables or the Kruskall-Wallis test for asymmetrically distributed variables. The effects of training intervention (time effect [baseline vs post-training] and group × time interaction effect) were assessed using two-way analysis of variance or analysis of covariance, where applicable. All analyses were performed with SPSS version 25 (IBM) with the P value of <.05. RESULTS Seventy-nine patients with CAD were randomized, and 59 patients completed the study (see Supplemental Digital Content 1, available at: https://links.lww.com/JCRP/A472). Patients were predominately males (75%), aged 61 ± 8 yr with a left ventricular ejection fraction of 53 ± 9%. The training group mostly shared similar demographic and clinical characteristics (see Supplemental Digital Content 2, available at: https://links.lww.com/JCRP/A473). Training groups differed only in baseline TNF-α levels (P = .048). After adjusting for baseline difference, there was no between-group difference in post-training TNF-α (P = .507). Training intervention had only time effect on CRP (P = .017), but there was no significant time × group interaction on any of the blood biomarkers (all Ps > .153; Figure). In addition, there was a borderline decrease in IGF-1 and CRP levels after LL-RT (−9 ng/mL, P = .075; Figure, part B) and HL-RT (−0.88 mg/L, P = .069; Figure, part C), respectively. The additional comparisons between combined RT modalities and AT alone also showed no between-group differences in post-training improvement of growth hormone (interaction, P = .226), IGF-1 (interaction, P = .276), CRP (interaction, P = .659), TNF-α (interaction, P = .746), and vascular endothelial growth factor levels (interaction, P = .131).Figure.: Anabolic and inflammatory profile at baseline and post-training. Data are presented as mean ± SD. Abbreviations: AT, aerobic training; CRP, C-reactive protein; GH, growth hormone; HL-RT, high-load resistance training; IGF-1, insulin-like growth factor 1; LL-RT, low-load resistance training; TNF-α, tumor necrosis factor alpha; VEGF, vascular endothelial growth factor. Time and time × group interaction present two-way analysis of variance results, and baseline effect and post-training present analysis of covariance results.DISCUSSION In contrast to recently shown superiority of HL-RT over LL-RT or AT alone in improvement of maximal muscle strength,8 this secondary analysis showed that none of the training interventions applied in the study had any effects on anabolic and inflammatory biomarkers. Most of the previous training interventions reported a reduction in CRP2–4 and ambiguous effects on TNF-α.2,5 Our study is aligned with previous findings in patients with CAD, which reported no benefit of a 4-wk AT training program on vascular endothelial growth factor.7 Nonetheless, most of the longer training interventions (>6 mo) in patients with CAD including whole-body RT reduced CRP levels to a greater extent than with AT or control.3,4 Whether such (longer) training modalities are feasible in clinical practice and, more importantly, whether this can be applied across Europe or globally is a true challenge for clinical medicine. Our training intervention was limited by a small sample size, a single RT exercise for lower limbs, and the absence of upper-body and trunk exercises, which would potentially elicit a greater anabolism and anti-inflammatory response. Therefore, future studies should better address the potential additional benefit of combined whole-body (HL-) RT with AT over traditionally prescribed AT.