Longitudinal Changes in Skeletal Muscle Metabolism, Oxygen Uptake, and Myosteatosis During Cardiotoxic Treatment for Early-Stage Breast Cancer.

BACKGROUND: While cardiotoxic chemotherapy is known to negatively impact cardiac function and hemoglobin levels, the impact on skeletal muscle has been understudied among patients. The purpose was to longitudinally characterize myosteatosis (muscle fat), skeletal muscle metabolism, and oxygen (O2) consumption during cardiotoxic chemotherapy for breast cancer. PATIENTS AND METHODS: Thirty-four patients with stage I-III breast cancer were enrolled before trastuzumab-containing and/or anthracycline-containing chemotherapy. We used magnetic resonance imaging to non-invasively quantify thigh myosteatosis (fat-water imaging), and lower leg metabolism (31P spectroscopy), O2 consumption (custom techniques), and peak power output during single-leg plantarflexion exercise at pre-, mid-, end-chemotherapy, and 1-year. We also measured pulmonary VO2peak and maximal leg press strength. RESULTS: During chemotherapy, VO2peak and leg press strength decreased while peak plantarflexion power output was maintained. At mid-chemotherapy, hemoglobin decreased (16%) and lower leg blood flow increased (37%) to maintain lower leg O2 delivery; exercise Pi:PCr and myosteatosis increased. Between mid- and end-chemotherapy, lower leg O2 extraction (28%) and O2 consumption (21%) increased, while plantarflexion exercise efficiency (watts/O2 consumed) decreased. At one year, VO2peak and leg press strength returned to pre-chemotherapy levels, but lower leg exercise O2 extraction, consumption and Pi:PCr, and myosteatosis remained elevated. CONCLUSION: Lower leg skeletal muscle blood flow and O2 extraction adapt to compensate for chemotherapy-related hemoglobin reduction for small muscle mass exercise but are insufficient to maintain large muscle mass exercise (pulmonary VO2peak, leg press strength). The excess O2 required to perform work, increased Pi:PCr ratio and myosteatosis together suggest suppressed fat oxidation during chemotherapy.

Cardiac and skeletal muscle predictors of impaired cardiorespiratory fitness post-anthracycline chemotherapy for breast cancer.

This study aimed to characterize peak exercise cardiac function and thigh muscle fatty infiltration and their relationships with VO2peak among anthracycline-treated breast cancer survivors (BCS). BCS who received anthracycline chemotherapy ~ 1 year earlier (n = 16) and matched controls (matched-CON, n = 16) were enrolled. Resting and peak exercise cardiac function, myocardial T1 mapping (marker of fibrosis), and thigh muscle fat infiltration were assessed by magnetic resonance imaging, and VO2peak by cycle test. Compared to matched-CON, BCS had lower peak SV (64 ± 9 vs 57 ± 10 mL/m2, p = 0.038), GLS (- 30.4 ± 2.2 vs - 28.0 ± 2.5%, p = 0.008), and arteriovenous oxygen difference (16.4 ± 3.6 vs 15.2 ± 3.9 mL/100 mL, p = 0.054). Mediation analysis showed: (1) greater myocardial T1 time (fibrosis) is inversely related to cardiac output and end-systolic volume exercise reserve; (2) greater thigh muscle fatty infiltration is inversely related to arteriovenous oxygen difference; both of which negatively influence VO2peak. Peak SV (R2 = 65%) and thigh muscle fat fraction (R2 = 68%) were similarly strong independent predictors of VO2peak in BCS and matched-CON combined. Post-anthracyclines, myocardial fibrosis is associated with impaired cardiac reserve, and thigh muscle fatty infiltration is associated with impaired oxygen extraction, which both contribute to VO2peak.

Aerobic Fitness Is Related to Myocardial Fibrosis Post-Anthracycline Therapy.

PURPOSE: We evaluated the impact of anthracyclines on left ventricular function and myocardial tissue characteristics using cardiovascular magnetic resonance (CMR) imaging to determine their relationship with V˙O2peak. METHODS: Women with breast cancer who had not yet received treatment (No-AT, n = 16) and had received anthracycline treatment ~1 yr earlier (Post-AT, n = 16) and controls without cancer (CON, n = 16) performed a maximal exercise test and a comprehensive 3T CMR examination, including native myocardial T1 mapping, where elevated T1 times are indicative of myocardial fibrosis. ANOVA and linear regression were used to compare CMR variables between groups and to determine associations with V˙O2peak. Subgroup analysis was performed by categorizing participants as "fit" or "unfit" based on whether their V˙O2peak value was greater or less than 100% of reference value for age, respectively. RESULTS: Left ventricular end-diastolic volume, ejection fraction, and mass were similar between groups. Post-AT, T1 times were elevated (1534 ± 32 vs 1503 ± 28 ms, P < 0.01), and V˙O2peak was reduced (23.1 ± 7.5 vs 29.5 ± 7.7 mL·kg-1⋅min-1, P = 0.02) compared with CON. In No-AT, T1 times and V˙O2peak were similar to CON. In the Post-AT group, T1 time was associated with V˙O2peak (R2 = 64%), whereas in the absence of anthracyclines (i.e., No-AT and CON groups), T1 time was not associated with V˙O2peak. Regardless of group, all fit women had similar T1 times, whereas unfit women Post-AT had higher T1 than unfit CON (1546 ± 22 vs 1500 ± 33 ms, P < 0.01). CONCLUSIONS: After anthracycline chemotherapy, an elevated T1 time suggesting greater extent of myocardial fibrosis, was associated with lower V˙O2peak. However, those who were fit did not have evidence of myocardial fibrosis after anthracycline treatment.

Exercise Intolerance in Anthracycline-Treated Breast Cancer Survivors: The Role of Skeletal Muscle Bioenergetics, Oxygenation, and Composition.

BACKGROUND: Peak oxygen consumption (VO2 ) is reduced in women with a history of breast cancer (BC). We measured leg blood flow, oxygenation, bioenergetics, and muscle composition in women with BC treated with anthracycline chemotherapy (n = 16, mean age: 56 years) and age- and body mass index-matched controls (n = 16). MATERIALS AND METHODS: Whole-body peak VO2 was measured during cycle exercise. 31 Phosphorus magnetic resonance (MR) spectroscopy was used to measure muscle bioenergetics during and after incremental to maximal plantar flexion exercise (PFE). MR imaging was used to measure lower leg blood flow, venous oxygen saturation (Sv O2 ), and VO2 during submaximal PFE, and abdominal, thigh, and lower leg intermuscular fat (IMF) and skeletal muscle (SM). RESULTS: Whole-body peak VO2 was significantly lower in BC survivors versus controls (23.1 ± 7.5 vs. 29.5 ± 7.7 mL/kg/minute). Muscle bioenergetics and mitochondrial oxidative capacity were not different between groups. No group differences were found during submaximal PFE for lower leg blood flow, Sv O2 , or VO2 . The IMF-to-SM ratio was higher in the thigh and lower leg in BC survivors (0.36 ± 0.19 vs. 0.22 ± 0.07, p = .01; 0.10 ± 0.06 vs. 0.06 ± 0.02, p = .03, respectively) and were inversely related to whole-body peak VO2 (r = -0.71, p = .002; r = -0.68, p = .003, respectively). In the lower leg, IMF-to-SM ratio was inversely related to VO2 and O2 extraction during PFE. CONCLUSION: SM bioenergetics and oxidative capacity in response to PFE are not impaired following anthracycline treatment. Abnormal SM composition (increased thigh and lower leg IMF-to-SM ratio) may be an important contributor to reduced peak VO2 during whole-body exercise among anthracycline-treated BC survivors. IMPLICATIONS FOR PRACTICE: Peak oxygen consumption (peak VO2 ) is reduced in breast cancer (BC) survivors and is prognostic of increased risk of cardiovascular disease-related and all-cause mortality. Results of this study demonstrated that in the presence of deficits in peak VO2 1 year after anthracycline therapy, skeletal muscle bioenergetics and oxygenation are not impaired. Rather, body composition deterioration (e.g., increased ratio of intermuscular fat to skeletal muscle) may contribute to reduced exercise tolerance in anthracycline BC survivors. This finding points to the importance of lifestyle interventions including caloric restriction and exercise training to restore body composition and cardiovascular health in the BC survivorship setting.