Predictors of Mortality in Pulmonary Hypertension-Associated Chronic Lung Disease.

Background/Objectives: Pulmonary hypertension (PH) often accompanies chronic lung diseases. Several chronic lung diseases with PH portends unfavorable outcomes. We investigated which variables in this cohort of patients with chronic lung disease and PH predicts mortality. Methods: This is a retrospective analysis of patients with chronic lung disease and PH at a single tertiary, academic center. The underlying lung disease included were COPD, IPF, other fibrotic ILD, non-fibrotic ILD, fibrotic sarcoidosis, and CPFE. All patients had right heart catheterization diagnostic of PH as well as pulmonary function testing data including 6 min walk testing. Univariable and multivariate Cox regression was performed to identify variables associated with mortality. Results: We identified 793 patients with chronic lung disease and PH. In total, 144 patients died prior to potential lung transplant. In multivariable Cox regression IPF, other fibrotic ILD, non-fibrotic ILD, and CPFE were significantly associated with an increased risk of mortality. Severe PH (PVR > 5 WU), FEV1 < 30% predicted, FVC < 40% predicted, 6 min walk distance < 150 m were also significantly associated with an increased risk of mortality. Conclusions: Carrying a diagnosis of IPF, CPFE, fibrotic ILD, or non-fibrotic ILD with PH has an increased risk of mortality as compared to COPD with PH. Hemodynamic, PVR > 5 WU, 6 min walk test less than 150 m, as well as spirometric data including FEV1 < 30% and FVC < 40% predicted were independently associated with an increased risk of death.

Effect of Triple Therapy with Budesonide-Formoterol-Tiotropium Versus Placebo-Tiotropium on Sleep Quality in Patients with Chronic Obstructive Pulmonary Disease.

BACKGROUND: Factors responsible for poor sleep quality in patients with chronic obstructive pulmonary disease (COPD) includes the effects of medications. This study evaluates the effect of the inhaled triple therapy of budesonide-formoterol-tiotropium versus placebo-tiotropium on sleep quality in COPD patients. METHODS: Twenty-three patients (11 [48%] males; age 55 [51-60, 48--5] years; body mass index [BMI] 25 [22-30, 18-40] kg/m2; forced expiratory volume in 1 second [FEV1]1.10 [0.80 -1.90, 0.60-2.80] L, 42 [31-62, 24-75] % predicted) were studied. Ten patients were randomized to budesonide-formoterol-tiotropium and 13 patients to placebo-tiotropium. At baseline and after 28 days, patients completed spirometry, polysomnography, an Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI), COPD-specific St George's Respiratory Questionnaire (SGRQ-C) and short form 36 (SF 36). RESULTS: After 28 days, there was a significant 29% increase in the bedtime FEV1 in the budesonide-formoterol-tiotropium group (from 0.75 [0.55-1.30, 0.50-2.40] L to 1.00 [0.75-1.55, 0.50-3.00] L, p=0.031), with no change in the placebo-tiotropium group (from 1.20 [0.80-1.50, 0.60-1.90] L to 1.15 [0.75-1.55, 0.50-1.80] L, p=0.91). No significant change was found post treatment in sleep efficiency or total sleep time in both the budesonide-formoterol-tiotropium group (from 78 [72-92, 62-98]% to 88 [77-92, 40-98]%, p=0.70 and 290 [268-358, 252-382] min to 342 [303-358, 157-372] min, p=0.77, respectively) and the placebo-tiotropium group (from 82 [75-88, 46-93]% to 84 [77-87, 62-94]%, p=0.96 and 320 [292-350, 180-378] min to 339 [303-349, 241-366] min, p=0.79, respectively). While there was no significant change in the arousal index in the budesonide-formoterol-tiotropium group (9 [5-16, 0-48] arousals/hour to 14 [9-17, 2-36] arousals/hour, p=0.43), a significant increase was seen in the placebo-tiotropium group (11 [4-13, 3--2] arousals/hour to 17 [11-21, 2-33] arousals/hour, p=0.027). Similarly, there was no change in the ESS in the budesonide-formoterol-tiotropium group (6 [3-8, 0-11] to 6 [5-8, 0-1]), p=0.44), but a marginally significant increase in the placebo-tiotropium group (8 [5-12, 2-18] to 10 [7-13, 5-18], p=0.07), with a significant difference in the ESS 28 days post treatment between the 2 groups (6 [5-8, 0-11] versus 10 [7-13, 5-18], p=0.043). There was no significant change in nocturnal oxygenation, sleep architecture, PSQI, SGRQ-C, or SF 36 in both groups. CONCLUSION: In patients with COPD, inhaled triple therapy with budesonide-formoterol-tiotropium as compared to placebo-tiotropium improves pulmonary function while preserving sleep quality and architecture.

Initial clinical and hemodynamic results of a regional pulmonary thromboendarterectomy program.

BACKGROUND: Pulmonary thromboendarterectomy (PTE) is the treatment of choice for eligible patients with chronic thromboembolic pulmonary hypertension (CTEPH). However, access to CTEPH and PTE care is limited. There is a paucity of published data on PTE efficacy and outcomes from alternative, regional centers of excellence in CTEPH and PTE care in the USA, outside a single national and international referral center. METHODS: We performed a retrospective review of patients undergoing PTE at our institution from June 2013 to December 2016 (42 months), and collected clinical, echocardiographic and hemodynamic data on our patients pre- and post-PTE (N.=71). RESULTS: Patients age ranged between 20-83 years (mean±SD: 56±16), with 54% of patients female and 61% Caucasians. The predominant symptom was shortness of breath with a median duration of symptoms of 17 months. Following PTE, clinical improvements included a reduction in NYHA class from 3.1±1.1 to 2.2±1.2. There were major improvements in hemodynamics and echocardiographic parameters pre- versus post-PTE: mean pulmonary artery pressure (mmHg) 45±11 to 24±8, cardiac index (L/min/m2) 2.1±0.5 to 2.8±0.5, pulmonary vascular resistance (mmHg/L/min) 8.9±4.5 to 2.8±1.8, ratio of right ventricle (RV): left ventricle (LV) 1.2±0.3 to 0.9±0.2, RV fractional area change (%) 23±14 to 44±13, reduction in the incidence of RV outflow tract Doppler notching and improved pulmonary artery acceleration time (96% to 30%, and 74±19 to 111±21). In-hospital mortality was 4.2% (3 patients). CONCLUSIONS: Herein, we report for the first time, the improvements in patient functionality, hemodynamics, right heart function and outcomes at a major regional PTE program.

Differences in right ventricular morphology, not function, indicate the nature of increased afterload in pulmonary hypertensive subjects with normal left ventricular function.

BACKGROUND: The aim of study was to assess whether a specific morphology of the right ventricle (RV) by 2D echo predicts the hemodynamic nature of pulmonary hypertension (PH). METHODS: We reviewed clinical, 2D echo, and hemodynamic data of 100 patients with PH: divided into three groups: PH from pulmonary vascular disease (PHPVD ; n = 34) with pulmonary vascular resistance (PVR) > 3 mm Hg/L/min (Wood unit [WU]) and pulmonary artery wedge pressure (PAWP) ≤ 15 mm Hg, pulmonary venous hypertension (PVH; n = 33) with PVR < 3 WU and PAWP > 15 mm Hg and PHMIXED (n = 33) with PVR > 3 WU and PAWP > 15 mm Hg. We analyzed several two-dimensional parameters of right heart morphology and function, including the degree of tapering of the RV diameter from base (just above tricuspid annulus) to apex (level of moderator band) in the apical four-chamber view. P = <.05. RESULTS: Baseline characteristics were similar in all three groups: age 62 ± 14.4 years, 69% females, 57% Caucasians. Hemodynamics and 2D echo data of PHPVD vs PVH vs PHMIXED were as follows: PVR 13 ± 6 vs 2 ± 1 vs 7 ± 2 WU, mean pulmonary artery pressure 53 ± 14 vs 34 ± 8 vs 49 ± 8 mm Hg and cardiac index 2.0 ± 0.5 vs 2.8 ± 0.7 vs 2.2 ± 0.7 L/m2 , RV base/apex ratio during systole (sRVb/a ) 1.3 ± 0.2 vs 2.6 ± 0.5 vs 1.5 ± 0.3. Thus, sRVb/a was twofold higher in the PVH vs PHPVD cohort. On ROC analysis, the AUC for sRVb/a for predicting PVR > 3 WU was 0.873, with optimal cutoff of 1.5. CONCLUSION: Systolic RV base/apex ratio is a simple 2D index of RV shape that powerfully predicts a PVR > 3 WU and provides powerful discriminating ability between PVH and PHPVD .

Tyrosine phosphorylation of the orphan receptor ESDN/DCBLD2 serves as a scaffold for the signaling adaptor CrkL.

A quantitative proteomics screen to identify substrates of the Src family of tyrosine kinases (SFKs) whose phosphorylation promotes CrkL-SH2 binding identified the known Crk-associated substrate (Cas) of Src as well as the orphan receptor endothelial and smooth muscle cell-derived neuropilin-like protein (ESDN). Mutagenesis analysis of ESDN's seven intracellular tyrosines in YxxP motifs found several contribute to the binding of ESDN to the SH2 domains of both CrkCT10 regulator of kinase Crk-Like (CrkL) and a representative SFK Fyn. Quantitative mass spectrometry showed that at least three of these (Y565, Y621 and Y750), as well as non-YxxP Y715, are reversibly phosphorylated. SFK activity was shown to be sufficient, but not required for the interaction between ESDN and the CrkL-SH2 domain. Finally, antibody-mediated ESDN clustering induces ESDN tyrosine phosphorylation and CrkL-SH2 binding.