We studied interrelationships between exercise endurance, ventilatory demand, operational lung volumes, and dyspnea during acute hyperoxia in ventilatory-limited patients with advanced chronic obstructive pulmonary disease (COPD). Eleven patients with COPD (FEV(1.0) = 31 +/- 3% predicted, mean +/- SEM) and chronic respiratory failure (Pa(O(2)) 52 +/- 2 mm Hg, Pa(CO(2 ))48 +/- 2 mm Hg) breathed room air (RA) or 60% O(2) during two cycle exercise tests at 50% of their maximal exercise capacity, in randomized order. Endurance time (T(lim)), dyspnea intensity (Borg Scale), ventilation (V E), breathing pattern, dynamic inspiratory capacity (IC(dyn)), and gas exchange were compared. Pa(O(2)) at end-exercise was 46 +/- 3 and 245 +/- 10 mm Hg during RA and O(2), respectively. During O(2), T(lim) increased 4.7 +/- 1.4 min (p < 0.001); slopes of Borg, V E, V CO(2), and lactate over time fell (p < 0.05); slopes of Borg-V E, V E-V CO(2), V E-lactate were unchanged. At a standardized time near end-exercise, O(2) reduced dyspnea 2.0 +/- 0.5 Borg units, V CO(2) 0.06 +/- 0.03 L/min, V E 2.8 +/- 1.0 L/min, and breathing frequency 4.4 +/- 1.1 breaths/min (p < 0.05 each). IC(dyn) and inspiratory reserve volume (IRV) increased throughout exercise with O(2) (p < 0.05). Increased IC(dyn) was explained by the combination of increased resting IRV and decreased exercise breathing frequency (r(2) = 0.83, p < 0.0005). In conclusion, improved exercise endurance during hyperoxia was explained, in part, by a combination of reduced ventilatory demand, improved operational lung volumes, and dyspnea alleviation.

We postulated that ventilatory assistance during exercise would improve cardiopulmonary function, relieve exertional symptoms, and increase exercise endurance (T(lim)) in patients with chronic congestive heart failure (CHF). After baseline pulmonary function tests, 12 stable patients with advanced CHF (ejection fraction, 24 +/- 3% [mean +/- SEM]) performed constant-load exercise tests at approximately 60% of their predicted maximal oxygen consumption (V O(2)max) while breathing each of control (1 cm H(2)O), continuous positive airway pressure optimized to the maximal tolerable level (CPAP = 4.8 +/- 0.2 cm H(2)O) or inspiratory pressure support (PS = 4.8 +/- 0.2 cm H(2)O), in randomized order. Measurements during exercise included cardioventilatory responses, esophageal pressure (Pes), and Borg ratings of dyspnea and leg discomfort (LD). At a standardized time near end-exercise, PS and CPAP reduced the work of breathing per minute by 39 +/- 8 and 25 +/- 4%, respectively (p < 0. 01). In response to PS: T(lim) increased by 2.8 +/- 0.8 min or 43 +/- 14% (p < 0.01); slopes of LD-time, V O(2)-time, V CO(2)-time, and tidal Pes-time decreased by 24 +/- 10, 20 +/- 11, 28 +/- 8, and 44 +/- 9%, respectively (p < 0.05); dyspnea and other cardioventilatory parameters did not change. CPAP did not significantly alter measured exercise responses. The increase in T(lim) was explained primarily by the decrease in LD- time slopes (r = -0.71, p < 0.001) which, in turn, correlated with the reductions in V O(2)-time (r = 0.61, p < 0.01) and tidal Pes-time (r = 0.52, p < 0.01). in conclusion, ventilatory muscle unloading with PS reduced exertional leg discomfort and increased exercise endurance in patients with stable advanced CHF.

Background: Pulmonary arterial hypertension (PAH) is a lethal vasculopathy. Hereditary cases are associated with germline mutations in BMPR2 and 16 other genes. However, these mutations occur in under 25% of idiopathic PAH patients (IPAH) and are rare in PAH associated with connective tissue diseases (APAH). Preclinical studies suggest epigenetic dysregulation, including altered DNA methylation, promotes PAH. Somatic mutations of Tet-methylcytosine-dioxygenase-2 (TET2), a key enzyme in DNA demethylation, occur in cardiovascular disease and are associated with clonal hematopoiesis, inflammation and adverse vascular remodeling. The role of TET2 in PAH is unknown. Methods: To test for a role of TET2, we utilized a cohort of 2572 cases from the PAH Biobank. Within this cohort, gene-specific rare variant association tests were performed using 1832 unrelated European PAH patients and 7509 non-Finnish European gnomAD subjects as controls. In an independent cohort of 140 patients, we quantified TET2 expression in peripheral blood mononuclear cells. To assess causality, we investigated hemodynamic and histologic evidence of PAH in hematopoietic Tet2-knockout mice. Results: We observed an increased burden of rare, predicted deleterious, germline variants in TET2 in PAH patients of European ancestry (9/1832) compared to controls (6/7509; relative risk=6, p=0.00067). Assessing the whole cohort, 0.39% (10/2572) of patients had 12 TET2 mutations (75% predicted germline and 25% somatic). These patients had no mutations in other PAH-related genes. Patients with TET2 mutations were older (71±7 years versus 48±19 years, p<0.0001) unresponsive to vasodilator challenge (0/7 vs 140/1055 (13.2%)), had lower PVR (5.2±3.1 versus 10.5±7.0 Woods units, p=0.02) and had increased inflammation (including elevation of IL-1β). Circulating TET2 expression did not correlate with age and was decreased in >86% of PAH patients. Tet2-knockout mice spontaneously developed PAH, adverse pulmonary vascular remodeling and inflammation, with elevated levels of cytokines, including IL-1β. Chronic therapy with an antibody targeting IL-1β blockade regressed PAH. Conclusions: PAH is the first human disease related to potential TET2 germline mutations. Inherited and acquired abnormalities of TET2 occur in 0.39% of PAH cases. Decreased TET2 expression is ubiquitous and has potential as a PAH biomarker.

In severe chronic obstructive pulmonary disease (COPD), carbon dioxide retention during exercise is highly variable and is poorly predicted by resting pulmonary function and arterial blood gases or by tests of ventilatory control. We reasoned that in patients with compromised gas exchange capabilities, exercise hypercapnia could be explained, in part, by the restrictive consequences of dynamic lung hyperinflation. We studied 20 stable patients with COPD (FEV(1) = 34 +/- 3 percent predicted; mean +/- SEM) with varying gas exchange abnormalities (Pa(O(2)) range, 35 to 84 mm Hg; Pa(CO(2)) range, 31 to 64 mm Hg). During symptom-limited maximum cycle exercise breathing room air, Pa(CO(2)) increased 7 +/- 1 mm Hg (p < 0.05) from rest to peak exercise (range, -6 to 25 mm Hg). We measured the change in Pa(CO(2)) after hyperoxic breathing at rest as an indirect test of ventilation-perfusion abnormalities. The change in Pa(CO(2)) from rest to peak exercise correlated best with the acute change in Pa(CO(2)) during hyperoxia at rest (r(2) = 0.62, p < 0.0005) and with resting arterial oxygen saturation (r(2) = 0.30, p = 0.011). During exercise, the strongest correlates of serial changes in Pa(CO(2)) from rest included concurrent changes in end-expiratory lung volume expressed as a percentage of total lung capacity (partial correlation coefficient [r] = 0.562, p < 0.0005) and oxygen saturation (partial r = 0.816, p < 0.0005). In severe COPD, the propensity to develop carbon dioxide retention during exercise reflects marked ventilatory constraints as a result of lung hyperinflation as well as reduced gas exchange capabilities.

Organization of metabolic pathways in vastus lateralis of patients with chronic obstructive pulmonary disease. Am J Physiol Regul Integr Comp Physiol 295: R935-R941, 2008. First published July 16, 2008 doi:10.1152/ajpregu.00167.2008.-The objective of this study was to determine whether patients with chronic obstructive lung disease (COPD) display differences in organization of the metabolic pathways and segments involved in energy supply compared with healthy control subjects. Metabolic pathway potential, based on the measurement of the maximal activity (Vmax) of representative enzymes, was assessed in tissue extracted from the vastus lateralis in seven patients with COPD (age 67 Ϯ 4 yr; FEV1/FVC ϭ 44 Ϯ 3%, where FEV1 is forced expiratory volume in 1 s and FVC is forced vital capacity; means Ϯ SE) and nine healthy age-matched controls (age 68 Ϯ 2 yr; FEV 1/FVC ϭ 75 Ϯ 2%). Compared with control, the COPD patients displayed lower (P Ͻ 0.05) Vmax (mol ⅐ kg protein Ϫ1 ⅐ h Ϫ1 ) for cytochrome c oxidase (COX; 21.2 Ϯ 2.0 vs. 28.7 Ϯ 2.2) and 3-hydroxyacyl-CoA dehydrogenase (HADH; 2.54 Ϯ 0.14 vs. 3.74 Ϯ 0.12) but not citrate synthase (CS; 2.20 Ϯ 0.16 vs. 3.19 Ϯ 0.5). While no differences between groups were observed in V max for creatine phosphokinase, phosphorylase (PHOSPH), phosphofructokinase (PFK), pyruvate kinase, and lactate dehydrogenase, hexokinase (HEX) was elevated in COPD (P Ͻ 0.05). Enzyme activity ratios were higher (P Ͻ 0.05) for HEX/CS, HEX/COX, PHOSPH/HADH and PFK/ HADH in COPD compared with control. It is concluded that COPD patients exhibit a reduced potential for both the electron transport system and fat oxidation and an increased potential for glucose phosphorylation while the potential for glycogenolysis and glycolysis remains normal. A comparison of enzyme ratios indicated greater potentials for glucose phosphorylation relative to the citric acid cycle and the electron transport chain and glycogenolysis and glycolysis relative to ␤-oxidation. lung disease; skeletal muscle; enzymes; oxidative; glycolytic.IT IS NOW GENERALLY ACCEPTED that submaximal contractile activity in patients with chronic obstructive pulmonary disease (COPD) is characterized by abnormal reductions in the content of high-energy phosphate bonds (phosphorylation potential) and excessive accumulation of lactic acid in muscle (15). These metabolic changes suggest an overemphasized dependence of high-energy phosphate transfer reactions and glycolysis to satisfy the energy needs of the working muscle (9).