Analysis of skeletal muscle gene expression patterns and the impact of functional capacity in patients with systolic heart failure.

BACKGROUND: Declining physical function is common among systolic heart failure (HF) patients and heralds poor clinical outcomes. We hypothesized that coordinated shifts in expression of ubiquitin-mediated atrophy-promoting genes are associated with muscle atrophy and contribute to decreased physical function. METHODS: Systolic HF patients (left ventricular ejection fraction [LVEF] ≤40%) underwent skeletal muscle biopsies (nondominant vastus lateralis) and comprehensive physical assessments. Skeletal muscle gene expression was assessed with the use of real-time polymerase chain reaction. Aerobic function was assessed with the use of cardiopulmonary exercise and 6-minute walk tests. Strength capacity was assessed with the use of pneumatic leg press (maximum strength and power). Serologic inflammatory markers also were assessed. RESULTS: 54 male patients (66.6 ± 10.0 years) were studied: 24 systolic HF patients (mean LVEF 28.9 ± 7.8%) and 30 age-matched control subjects. Aerobic and strength parameters were diminished in HF versus control. FoxO1 and FoxO3 were increased in HF versus control (7.9 ± 6.2 vs 5.0 ± 3.5, 6.5 ± 4.3 vs 4.3 ± 2.8 relative units, respectively; P ≤ .05 in both). However, atrogin-1 and MuRF-1 were similar in both groups. PGC-1α was also increased in HF (7.9 ± 5.4 vs. 5.3 ± 3.6 relative units; P < .05). Muscle levels of insulin-like growth factor (IGF) 1 as well as serum levels of tumor necrosis factor α, C-reactive protein, interleukin (IL) 1ß, and IL-6 were similar in HF and control. CONCLUSION: Expression of the atrophy-promoting genes FoxO1 and FoxO3 were increased in skeletal muscle in systolic HF compared with control, but other atrophy gene expression patterns (atrogin-1 and MuRF-1), as well as growth promoting patterns (IGF-1), were similar. PGC-1α, a gene critical in enhancing mitochondrial function and moderating FoxO activity, may play an important counterregulatory role to offset ubiquitin pathway-mediated functional decrements.

Dynamic assessment of ventilatory efficiency during recovery from peak exercise to enhance cardiopulmonary exercise testing.

BACKGROUND: While cardiopulmonary exercise testing (CPX) assessment is generally regarded as an optimal means to assess functional capacity in heart failure (HF) patients, strength parameters are omitted. CPX indices collected in recovery may provide additional insight regarding function, including strength. DESIGN AND METHODS: We performed a cross-sectional controlled study. Systolic HF patients (aged ≥ 50 years) and age-matched controls were assessed using CPX and strength evaluations. Standard CPX indices were assessed during exercise (peak oxygen consumption [VO2], first ventilatory threshold [1stVT], and ventilatory efficiency [VE/VCO2 slope]) as well as indices at 1-minute recovery (1 min VO2, 1 min VE/VCO2, and 1 min heart rate recovery [HRR]) and differences between peak and 1-minute recovery (ΔVO2 and ΔVE/VCO2). Lower extremity strength was evaluated using the 1-repetition maximum (1RM) and power. RESULTS: Seventy adults (31 HF; 39 controls), mean age 66.2 ± 9.7 years were evaluated. Peak VO2 (15.4 ± 4.2 versus 23.4 ± 6.6 mlO2·kg(-1)·min(-1), p < 0.0001) and 1stVT (10.9 ± 2.1 versus 14.4 ± 4.0 mlO2·kg(-1)·min(-1), p < 0.0001) were diminished in HF versus controls and VE/VCO2 slope was increased (42.3 ± 12.2 versus 35.4 ± 8.3, p < 0.01). HF patients had reduced 1 minVO2 (13.1 ± 2.9 versus 16.3 ± 3.7 mlO2·kg(-1)·min(-1), p < 0.0001), 1 min HRR (6.7 ± 11.4 versus 12.4 ± 7.6 beats, p < 0.02), and ΔVO2 (2.43 ± 2.3 versus 7.3 ± 5.0 mlO2·kg(-1)·min(-1), p < 0.0001) as well as increased 1 min VE/VCO2 (37 ± 7.5 versus 31.5 ± 4.4, p < 0.001) and ΔVE/VCO2 (1.17 ± 3.0 versus -0.5 ± 1.3, p < 0.0001). Strength parameters were relatively lower in HF. While CPX exercise parameters correlated with strength, stronger correlations were observed between CPX recovery parameters and strength. CONCLUSIONS: CPX recovery indices corroborate disease-specific aerobic differences and distinguish differences in strength. Recovery ventilatory efficiency enhances CPX's value as a comprehensive physical function tool.

Adiposity facilitates increased strength capacity in heart failure patients with reduced ejection fraction.

BACKGROUND: Obesity is associated with relatively improved prognosis among heart failure (HF) patients. Mechanisms explaining this so-called "obesity paradox" have been unclear. We hypothesized that increased adiposity may contribute to increased strength capacity, and may thereby facilitate clinical benefits. METHODS AND RESULTS: In a controlled, cross-sectional study, adults aged ≥ 50 years with HF with reduced ejection fraction (HFREF) (LVEF ≤ 40%) were compared to age matched controls. Body composition was determined by dual-energy X-ray absorptiometry (DXA). Aerobic (cardiopulmonary exercise testing), maximum strength (one repetition maximum [1RM]), and power (submaximal resistance/time) were assessed. 70 adults (31 HFREF, 39 controls; mean age 66.2 ± 9.6 years) were studied. Peak oxygen consumption (VO2) (15.4 ± 4.2 vs. 23.4 ± 6.6 ml O2 · kg(-1) · min(-1), p<0.0001), 1RM (154.8 ± 52.0 vs. 195.3 ± 56.8 kg, p<0.01) and power (226.4 ± 99.2 vs. 313.3 ± 130.6, p<0.01) were lower in HFREF vs. controls. 1 RM correlated with total fat (r=0.56, p<0.01), leg fat (r=0.45, p<0.05) and arm fat (r=0.39, p<0.05) in HFREF. Moreover, among HFREF patients with a high (≥ 30 kg/m(2)) body mass index (BMI), 1RM and fat mass were significantly greater than those with lower (<30 kg/m(2)) BMIs. Correlations between 1 RM and total fat (r=0.65, p<0.05) and leg fat (r=0.64, p<0.05) were particularly notable in the high BMI subgroup. CONCLUSION: Increased adiposity correlates with relatively greater strength in HFREF patients which may explain some of the clinical benefits that result from obesity.

Expression of the irisin precursor FNDC5 in skeletal muscle correlates with aerobic exercise performance in patients with heart failure.

BACKGROUND: Exercise-induced increase in peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) expression has been shown to increase the expression of the fibronectin type III domain containing 5 (FNDC5) gene and thereby its product, irisin, in mice. Given that exercise intolerance is a hallmark characteristic of heart failure (HF), and because PGC-1α and irisin promote exercise benefits in animals, we hypothesized that expression of these genes relates to aerobic performance in patients with HF. METHODS AND RESULTS: Systolic HF (left ventricular ejection fraction ≤40%) patients underwent cardiopulmonary exercise testing to evaluate aerobic performance. High versus low aerobic performance was assessed using oxygen consumption (peak Vo(2) [>14 versus ≤14 mL O(2)·kg(-1)·min(-1)]) and ventilatory efficiency (VE/Vco(2) slope [<34 versus ≥34]). Muscle biopsies of the vastus lateralis and real-time polymerase chain reaction were used to quantify muscle gene expression. Twenty-four patients were studied. FNDC5 (5.7±3.5 versus 3.1±1.2, P<0.05) and PGC-1α (9.9±5.9 versus 4.5±1.9, P<0.01) gene expressions were greater in the high-peak Vo(2) group; correlation between FNDC5 and PGC-1α was significant (r=0.56, P<0.05) only in the high-peak Vo(2) group. Similarly, FNDC5 and PGC-1α gene expression was greater in the high-performance group based on lower VE/Vco(2) slopes (5.8±3.6 versus 3.3±1.4, P<0.05 and 9.7±6 versus 5.3±3.4, P<0.05); FNDC5 also correlated with PGC-1α (r=0.55, P<0.05) only in the low VE/Vco(2) slope group. CONCLUSIONS: This is the first study to show that FNDC5 expression relates to functional capacity in a human HF population. Lower FNDC5 expression may underlie reduced aerobic performance in HF patients.