Peripheral Blood Mononuclear Cell Gene Expression Associated with Pulmonary Microvascular Perfusion: The Multi-Ethnic Study of Atherosclerosis Chronic Obstructive Pulmonary Disease.

Rationale: Chronic obstructive pulmonary disease (COPD) and emphysema are associated with endothelial damage and altered pulmonary microvascular perfusion. The molecular mechanisms underlying these changes are poorly understood in patients, in part because of the inaccessibility of the pulmonary vasculature. Peripheral blood mononuclear cells (PBMCs) interact with the pulmonary endothelium. Objectives: To test the association between gene expression in PBMCs and pulmonary microvascular perfusion in COPD. Methods: The Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study recruited two independent samples of COPD cases and controls with ⩾10 pack-years of smoking history. In both samples, pulmonary microvascular blood flow, pulmonary microvascular blood volume, and mean transit time were assessed on contrast-enhanced magnetic resonance imaging, and PBMC gene expression was assessed by microarray. Additional replication was performed in a third sample with pulmonary microvascular blood volume measures on contrast-enhanced dual-energy computed tomography. Differential expression analyses were adjusted for age, gender, race/ethnicity, educational attainment, height, weight, smoking status, and pack-years of smoking. Results: The 79 participants in the discovery sample had a mean age of 69 ± 6 years, 44% were female, 25% were non-White, 34% were current smokers, and 66% had COPD. There were large PBMC gene expression signatures associated with pulmonary microvascular perfusion traits, with several replicated in the replication sets with magnetic resonance imaging (n = 47) or dual-energy contrast-enhanced computed tomography (n = 157) measures. Many of the identified genes are involved in inflammatory processes, including nuclear factor-κB and chemokine signaling pathways. Conclusions: PBMC gene expression in nuclear factor-κB, inflammatory, and chemokine signaling pathways was associated with pulmonary microvascular perfusion in COPD, potentially offering new targetable candidates for novel therapies.

Causal determinants of postoperative length of stay in cardiac surgery using causal graphical learning.

OBJECTIVE: We aimed to learn the causal determinants of postoperative length of stay in cardiac surgery patients undergoing isolated coronary artery bypass grafting or aortic valve replacement surgery. METHODS: For patients undergoing isolated coronary artery bypass grafting or isolated aortic valve replacement surgeries between 2011 and 2016, we used causal graphical modeling on electronic health record data. The Fast Causal Inference (FCI) algorithm from the Tetrad software was used on data to estimate a Partial Ancestral Graph (PAG) depicting direct and indirect causes of postoperative length of stay, given background clinical knowledge. Then, we used the latent variable intervention-calculus when the directed acyclic graph is absent (LV-IDA) algorithm to estimate strengths of causal effects of interest. Finally, we ran a linear regression for postoperative length of stay to contrast statistical associations with what was learned by our causal analysis. RESULTS: In our cohort of 2610 patients, the mean postoperative length of stay was 219 hours compared with the Society of Thoracic Surgeons 2016 national mean postoperative length of stay of approximately 168 hours. Most variables that clinicians believe to be predictors of postoperative length of stay were found to be causes, but some were direct (eg, age, diabetes, hematocrit, total operating time, and postoperative complications), and others were indirect (including gender, race, and operating surgeon). The strongest average causal effects on postoperative length of stay were exhibited by preoperative dialysis (209 hours); neuro-, pulmonary-, and infection-related postoperative complications (315 hours, 89 hours, and 131 hours, respectively); reintubation (61 hours); extubation in operating room (-47 hours); and total operating room duration (48 hours). Linear regression coefficients diverged from causal effects in magnitude (eg, dialysis) and direction (eg, crossclamp time). CONCLUSIONS: By using retrospective electronic health record data and background clinical knowledge, causal graphical modeling retrieved direct and indirect causes of postoperative length of stay and their relative strengths. These insights will be useful in designing clinical protocols and targeting improvements in patient management.

Mapping Alveolar Oxygen Partial Pressure in COPD Using Hyperpolarized Helium-3: The Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study.

Chronic obstructive pulmonary disease (COPD) and emphysema are characterized by functional and structural damage which increases the spaces for gaseous diffusion and impairs oxygen exchange. Here we explore the potential for hyperpolarized (HP) 3He MRI to characterize lung structure and function in a large-scale population-based study. Participants (n = 54) from the Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study, a nested case-control study of COPD among participants with 10+ packyears underwent HP 3He MRI measuring pAO2, apparent diffusion coefficient (ADC), and ventilation. HP MRI measures were compared to full-lung CT and pulmonary function testing. High ADC values (>0.4 cm2/s) correlated with emphysema and heterogeneity in pAO2 measurements. Strong correlations were found between the heterogeneity of global pAO2 as summarized by its standard deviation (SD) (p < 0.0002) and non-physiologic pAO2 values (p < 0.0001) with percent emphysema on CT. A regional study revealed a strong association between pAO2 SD and visual emphysema severity (p < 0.003) and an association with the paraseptal emphysema subtype (p < 0.04) after adjustment for demographics and smoking status. HP noble gas pAO2 heterogeneity and the fraction of non-physiological pAO2 results increase in mild to moderate COPD. Measurements of pAO2 are sensitive to regional emphysematous damage detected by CT and may be used to probe pulmonary emphysema subtypes. HP noble gas lung MRI provides non-invasive information about COPD severity and lung function without ionizing radiation.