Identification of male COPD patients with exertional hypoxemia who may benefit from long-term oxygen therapy.

Several studies have documented increased exercise capacity with supplemental oxygen therapy in patients with COPD and exertional hypoxemia, but a large trial failed to demonstrate a survival benefit in this population. Due to the heterogeneity observed in therapeutic responses, we sought to retrospectively evaluate survival in male COPD patients with exertional hypoxemia who had a clinically meaningful improvement in exercise capacity while using supplemental oxygen compared to their 6-minute walk test distance (6MWD) while walking on room air. We defined them as responders or non-responders based on a change in 6MWD of greater or less than 54m. We compared their clinical and physiologic characteristics, and their survival over time. From 817 COPD subjects who underwent an assessment for home oxygen during the study period, 140 met inclusion criteria, with 70 (50%) qualifying as responders. There were no significant differences in demographics, lung function, or baseline oxygenation between the groups. The only difference noted was in the baseline 6MWD on room air, with responders to oxygen therapy having significantly lower values (137 ± 74m, 27 ± 15% predicted) compared to non-responders (244 ± 108, 49 ± 23% predicted). Despite their poorer functional capacity, mortality was significantly lower in responders after adjusting for age, comorbidities, and FEV1 (HR 0.51; CI 0.31-0.83; p = 0.007) compared to non-responders after a median follow-up time of 3 years. We conclude that assessing the immediate effects of oxygen on exercise capacity may be an important way to identify individuals with exertional hypoxemia who may benefit in the long-term from ambulatory oxygen. Prospective long-term studies in this subset of patients with exercise induced hypoxemia are warranted

Identification of male COPD patients with exertional hypoxemia who may benefit from long-term oxygen therapy

Several studies have documented increased exercise capacity with supplemental oxygen therapy in patients with COPD and exertional hypoxemia, but a large trial failed to demonstrate a survival benefit in this population. Due to the heterogeneity observed in therapeutic responses, we sought to retrospectively evaluate survival in male COPD patients with exertional hypoxemia who had a clinically meaningful improvement in exercise capacity while using supplemental oxygen compared to their 6-minute walk test distance (6MWD) while walking on room air. We defined them as responders or non-responders based on a change in 6MWD of greater or less than 54m. We compared their clinical and physiologic characteristics, and their survival over time. From 817 COPD subjects who underwent an assessment for home oxygen during the study period, 140 met inclusion criteria, with 70 (50%) qualifying as responders. There were no significant differences in demographics, lung function, or baseline oxygenation between the groups. The only difference noted was in the baseline 6MWD on room air, with responders to oxygen therapy having significantly lower values (137 ± 74m, 27 ± 15% predicted) compared to non-responders (244 ± 108, 49 ± 23% predicted). Despite their poorer functional capacity, mortality was significantly lower in responders after adjusting for age, comorbidities, and FEV1 (HR 0.51; CI 0.31–0.83; p = 0.007) compared to non-responders after a median follow-up time of 3 years. We conclude that assessing the immediate effects of oxygen on exercise capacity may be an important way to identify individuals with exertional hypoxemia who may benefit in the long-term from ambulatory oxygen. Prospective long-term studies in this subset of patients with exercise induced hypoxemia are warranted

NLRP3 inflammasome is a key driver of obesity-induced atrial arrhythmias

AIMS: Obesity, an established risk factor of atrial fibrillation (AF), is frequently associated with enhanced inflammatory response. However, whether inflammatory signaling is causally linked to AF pathogenesis in obesity remains elusive. We recently demonstrated that the constitutive activation of the ‘NACHT, LRR, and PYD Domains-containing Protein 3’ (NLRP3) inflammasome promotes AF susceptibility. In this study, we hypothesized that the NLRP3 inflammasome is a key driver of obesity-induced AF. METHODS AND RESULTS: Western blotting was performed to determine the level of NLRP3 inflammasome activation in atrial tissues of obese patients, sheep, and diet-induced obese (DIO) mice. The increased body weight in patients, sheep, and mice was associated with enhanced NLRP3-inflammasome activation. To determine whether NLRP3 contributes to the obesity-induced atrial arrhythmogenesis, wild-type (WT) and NLRP3 homozygous knockout (NLRP3(−/−)) mice were subjected to high-fat-diet (HFD) or normal chow (NC) for 10 weeks. Relative to NC-fed WT mice, HFD-fed WT mice were more susceptible to pacing-induced AF with longer AF duration. In contrast, HFD-fed NLRP3(−/−) mice were resistant to pacing-induced AF. Optical mapping in DIO mice revealed an arrhythmogenic substrate characterized by abbreviated refractoriness and action potential duration (APD), two key determinants of reentry-promoting electrical remodeling. Upregulation of ultra-rapid delayed-rectifier K(+)-channel (Kv1.5) contributed to the shortening of atrial refractoriness. Increased profibrotic signaling and fibrosis along with abnormal Ca(2+) release from sarcoplasmic reticulum (SR) accompanied atrial arrhythmogenesis in DIO mice. Conversely, genetic ablation of Nlrp3 (NLRP3(−/−)) in HFD-fed mice prevented the increases in Kv1.5 and the evolution of electrical remodeling, the upregulation of profibrotic genes, and abnormal SR Ca(2+) release in DIO mice. CONCLUSION: These results demonstrate that the atrial NLRP3 inflammasome is a key driver of obesity-induced atrial arrhythmogenesis and establishes a mechanistic link between obesity-induced AF and NLRP3-inflammasome activation