Impaired Spontaneous Baroreceptor Reflex Sensitivity in Patients With COPD Compared to Healthy Controls: The Role of Lung Hyperinflation.

Background and Objectives: Patients with chronic obstructive pulmonary disease (COPD) are at increased risk for cardiovascular disease. This study aimed to investigate the relationship between pulmonary hyperinflation and baroreceptor reflex sensitivity (BRS), a surrogate for cardiovascular risk. Methods: 33 patients with COPD, free from clinical cardiovascular disease, and 12 healthy controls were studied. Participants underwent pulmonary function and non-invasive hemodynamic measurements. BRS was evaluated using the sequence method during resting conditions and mental arithmetic stress testing. Results: Patients with COPD had evidence of airflow obstruction [forced expiratory volume in 1 s predicted (FEV1%) 26.5 (23.3-29.1) vs. 91.5 (82.8-100.8); P < 0.001; geometric means (GM) with 95% confidence interval (CI)] and lung hyperinflation [residual volume/total lung capacity (RV/TLC) 67.7 (64.3-71.3) vs. 41.0 (38.8-44.3); P < 0.001; GM with 95% CI] compared to controls. Spontaneous mean BRS (BRSmean) was significantly lower in COPD, both during rest [5.6 (4.2-6.9) vs. 12.0 (9.1-17.6); P = 0.003; GM with 95% CI] and stress testing [4.4 (3.7-5.3) vs. 9.6 (7.7-12.2); P < 0.001; GM with 95% CI]. Stroke volume (SV) was significantly lower in the patient group [-21.0 ml (-29.4 to -12.6); P < 0.001; difference of the means with 95% CI]. RV/TLC was found to be a predictor of BRS and SV (P < 0.05 for both), independent of resting heart rate. Conclusion: We herewith provide evidence of impaired BRS in patients with COPD. Hyperinflation may influence BRS through alteration of mechanosensitive vagal nerve activity.

Respiratory Sinus Arrhythmia Attenuation via Targeted Lung Denervation in Sheep and Humans.

BACKGROUND: Targeted lung denervation (TLD) is a novel bronchoscopic therapy that disrupts parasympathetic pulmonary nerve input to the lung. Parasympathetic input to the heart originating from the lungs contributes to respiratory sinus arrhythmia (RSA) and disruption of pulmonary nerves via TLD may impact RSA. OBJECTIVE: The aim of this study was to assess the potential of TLD to affect RSA in sheep and humans. METHODS: TLD was performed in 5 sheep and 9 humans using a novel lung denervation system (Nu-vaira Inc., Minneapolis, MN, USA) with an electrocardiogram collected before and after the procedure. Frequency domain analysis of heart rate variability was performed in 5 sheep and 6 humans with presence of RSA approximated as high-frequency power (HF power). RESULTS: HF power decreased in 3 of 5 sheep with 1 animal reaching less than 7% of its baseline HF power 30 days after TLD. The average treatment location was more distal in the remaining 2 animals, which did not exhibit RSA attenuation, suggesting diminished denervation. HF power decreased in 5 of 6 humans, with 3 subjects reaching less than 50% of their baseline HF power 90 days after TLD. CONCLUSIONS: TLD appeared to attenuate RSA in both sheep and human cohorts of this sub-study. Further confirmation in humans is necessary to allow for RSA attenuation to be used as a marker of successful lung denervation via TLD.

Long-term safety of bilateral targeted lung denervation in patients with COPD.

Background: Targeted lung denervation (TLD) is a novel bronchoscopic therapy for COPD which ablates parasympathetic pulmonary nerves running along the outside of the two main bronchi with the intent of inducing permanent bronchodilation. The goal of this study was to evaluate the feasibility and long-term safety of bilateral TLD during a single procedure. Patients and methods: This prospective, multicenter study evaluated 15 patients with moderate-to-severe COPD (forced expiratory volume in 1 s [FEV1] 30%-60%) who underwent bilateral TLD treatment following baseline assessment without bronchodilators. The primary safety end point was freedom from documented and sustained worsening of COPD directly attributable to TLD up to 1 year. Secondary end points included technical feasibility, change in pulmonary function tests, exercise capacity, and health-related quality of life. Follow-up continued up to 3 years for subjects who reconsented for longer-term follow-up. Results: A total of 15 patients (47% male, age 63.2±4.0 years) underwent TLD with a total procedure time of 89±16 min, and the total fluoroscopy time was 2.5±2.7 min. Primary safety end point of freedom from worsening of COPD was 100%. There were no procedural complications reported. Results of lung function analysis and exercise capacity demonstrated similar beneficial effects of TLD without bronchodilators, when compared with long-acting anticholinergic therapy at 30 days, 180 days, 365 days, 2 years, and 3 years post-TLD. Five of the 12 serious adverse events that were reported through 3 years of follow-up were respiratory related with no events being related to TLD therapy. Conclusion: TLD delivered to both lungs in a single procedure is feasible and safe with few respiratory-related adverse events through 3 years.

Physiological modeling of responses to upper versus lower lobe lung volume reduction in homogeneous emphysema.

RATIONALE: In clinical trials, homogeneous emphysema patients have responded well to upper lobe volume reduction but not lower lobe volume reduction. MATERIALS/METHODS: To understand the physiological basis for this observation, a computer model was developed to simulate the effects of upper and lower lobe lung volume reduction on RV/TLC and lung recoil in homogeneous emphysema. RESULTS: Patients with homogeneous emphysema received either upper or lower lobe volume reduction therapy based on findings of radionucleotide scintigraphy scanning. CT analysis of lobar volumes showed that patients undergoing upper (n = 18; -265 mL/site) and lower lobe treatment (LLT; n = 11; -217 mL/site) experienced similar reductions in lung volume. However, only upper lobe treatment (ULT) improved FEV(1) (+11.1 ± 14.7 versus -4.4 ± 15.8%) and RV/TLC (-5.4 ± 8.1 versus -2.4 ± 8.6%). Model simulations provided an unexpected explanation for this response. Increases in transpulmonary pressure subsequent to volume reduction increased RV/TLC in upper lobe alveoli, while caudal shifts in airway closure decreased RV/TLC in lower lobe alveoli. ULT, which eliminates apical alveoli with high RV/TLC values, lowers the average RV/TLC of the lung. Conversely, LLT, which eliminates caudal alveoli with low RV/TLC values, has less effect. CONCLUSION: LLT in homogeneous emphysema is uniformly less effective than ULT.