Effects of inspiratory muscle training combined with aerobic exercise training on neurovascular control in chronic heart failure patients.

AIMS: We tested the hypothesis that the effects of combined inspiratory muscle training and aerobic exercise training (IMT + AET) on muscle sympathetic nerve activity (MSNA) and forearm blood flow in patients with heart failure with reduced ejection fraction are more pronounced than the effects of AET alone. METHODS AND RESULTS: Patients aged 30-70 years, New York Heart Association Functional Class II-III, and left ventricular ejection fraction ≤40% were randomly assigned to four groups: IMT (n = 11), AET (n = 12), IMT + AET (n = 9), and non-training (NT; n = 10). MSNA was recorded using microneurography. Forearm blood flow was measured by venous occlusion plethysmography and inspiratory muscle strength by maximal inspiratory pressure. IMT consisted of 30 min sessions, five times a week, for 4 months. Moderate AET consisted of 60 min sessions, three times a week for 4 months. AET (-10 ± 2 bursts/min, P = 0.03) and IMT + AET (-13 ± 4 bursts/min, P = 0.007) reduced MSNA. These responses in MSNA were not different between AET and IMT + AET groups. IMT (0.22 ± 0.08 mL/min/100 mL, P = 0.03), AET (0.27 ± 0.09 mL/min/100 mL, P = 0.01), and IMT + AET (0.35 ± 0.12 mL/min/100 mL, P = 0.008) increased forearm blood flow. No differences were found between groups. AET (3 ± 1 mL/kg/min, P = 0.006) and IMT + AET (4 ± 1 mL/kg/min, P = 0.001) increased peak oxygen consumption. These responses were similar between these groups. IMT (20 ± 3 cmH2 O, P = 0.005) and IMT + AET (18 ± 3 cmH2 O, P = 0.01) increased maximal inspiratory pressure. No significant changes were observed in the NT group. CONCLUSIONS: IMT + AET causes no additive effects on neurovascular control in patients with heart failure with reduced ejection fraction compared with AET alone. These findings may be, in part, because few patients had inspiratory muscle weakness.

Effects of aerobic and inspiratory training on skeletal muscle microRNA-1 and downstream-associated pathways in patients with heart failure.

BACKGROUND: The exercise intolerance in chronic heart failure with reduced ejection fraction (HFrEF) is mostly attributed to alterations in skeletal muscle. However, the mechanisms underlying the skeletal myopathy in patients with HFrEF are not completely understood. We hypothesized that (i) aerobic exercise training (AET) and inspiratory muscle training (IMT) would change skeletal muscle microRNA-1 expression and downstream-associated pathways in patients with HFrEF and (ii) AET and IMT would increase leg blood flow (LBF), functional capacity, and quality of life in these patients. METHODS: Patients age 35 to 70 years, left ventricular ejection fraction (LVEF) ≤40%, New York Heart Association functional classes II-III, were randomized into control, IMT, and AET groups. Skeletal muscle changes were examined by vastus lateralis biopsy. LBF was measured by venous occlusion plethysmography, functional capacity by cardiopulmonary exercise test, and quality of life by Minnesota Living with Heart Failure Questionnaire. All patients were evaluated at baseline and after 4 months. RESULTS: Thirty-three patients finished the study protocol: control (n = 10; LVEF = 25 ± 1%; six males), IMT (n = 11; LVEF = 31 ± 2%; three males), and AET (n = 12; LVEF = 26 ± 2%; seven males). AET, but not IMT, increased the expression of microRNA-1 (P = 0.02; percent changes = 53 ± 17%), decreased the expression of PTEN (P = 0.003; percent changes = -15 ± 0.03%), and tended to increase the p-AKTser473 /AKT ratio (P = 0.06). In addition, AET decreased HDAC4 expression (P = 0.03; percent changes = -40 ± 19%) and upregulated follistatin (P = 0.01; percent changes = 174 ± 58%), MEF2C (P = 0.05; percent changes = 34 ± 15%), and MyoD expression (P = 0.05; percent changes = 47 ± 18%). AET also increased muscle cross-sectional area (P = 0.01). AET and IMT increased LBF, functional capacity, and quality of life. Further analyses showed a significant correlation between percent changes in microRNA-1 and percent changes in follistatin mRNA (P = 0.001, rho = 0.58) and between percent changes in follistatin mRNA and percent changes in peak VO2 (P = 0.004, rho = 0.51). CONCLUSIONS: AET upregulates microRNA-1 levels and decreases the protein expression of PTEN, which reduces the inhibitory action on the PI3K-AKT pathway that regulates the skeletal muscle tropism. The increased levels of microRNA-1 also decreased HDAC4 and increased MEF2c, MyoD, and follistatin expression, improving skeletal muscle regeneration. These changes associated with the increase in muscle cross-sectional area and LBF contribute to the attenuation in skeletal myopathy, and the improvement in functional capacity and quality of life in patients with HFrEF. IMT caused no changes in microRNA-1 and in the downstream-associated pathway. The increased functional capacity provoked by IMT seems to be associated with amelioration in the respiratory function instead of changes in skeletal muscle. ClinicalTrials.gov (Identifier: NCT01747395).

A Cycle Ergometer Exercise Program Improves Exercise Capacity and Inspiratory Muscle Function in Hospitalized Patients Awaiting Heart Transplantation: a Pilot Study.

Objective: The purpose of this study was to evaluate the effect of a cycle ergometer exercise program on exercise capacity and inspiratory muscle function in hospitalized patients with heart failure awaiting heart transplantation with intravenous inotropic support. Methods: Patients awaiting heart transplantation were randomized and allocated prospectively into two groups: 1) Control Group (n=11) - conventional protocol; and 2) Intervention Group (n=7) - stationary cycle ergometer exercise training. Functional capacity was measured by the six-minute walk test and inspiratory muscle strength assessed by manovacuometry before and after the exercise protocols. Results: Both groups demonstrated an increase in six-minute walk test distance after the experimental procedure compared to baseline; however, only the intervention group had a significant increase (P =0.08 and P =0.001 for the control and intervention groups, respectively). Intergroup comparison revealed a greater increase in the intervention group compared to the control (P <0.001). Regarding the inspiratory muscle strength evaluation, the intragroup analysis demonstrated increased strength after the protocols compared to baseline for both groups; statistical significance was only demonstrated for the intervention group, though (P =0.22 and P <0.01, respectively). Intergroup comparison showed a significant increase in the intervention group compared to the control (P <0.01). Conclusion: Stationary cycle ergometer exercise training shows positive results on exercise capacity and inspiratory muscle strength in patients with heart failure awaiting cardiac transplantation while on intravenous inotropic support.