Hypoxia-induced endothelial CX3CL1 triggers lung smooth muscle cell phenotypic switching and proliferative expansion.

Distal arterioles with limited smooth muscles help maintain the high blood flow and low pressure in the lung circulation. Chronic hypoxia induces lung distal vessel muscularization. However, the molecular events that trigger alveolar hypoxia-induced peripheral endothelium modulation of vessel wall smooth muscle cell (SMC) proliferation and filling of nonmuscular areas are unclear. Here, we investigated the role of CX3CL1/CX3CR1 system in endothelial-SMC cross talk in response to hypoxia. Human lung microvascular endothelial cells responded to alveolar oxygen deficiency by overproduction of the chemokine CX3CL1. The CX3CL1 receptor CX3CR1 is expressed by SMCs that are adjacent to the distal endothelium. Hypoxic release of endothelial CX3CL1 induced SMC phenotypic switching from the contractile to the proliferative state. Inhibition of CX3CR1 prevented CX3CL1 stimulation of SMC proliferation and monolayer expansion. Furthermore, CX3CR1 deficiency attenuated spiral muscle expansion, distal vessel muscularization, and pressure elevation in response to hypoxia. Our findings indicate that the capillary endothelium relies on the CX3CL1-CX3CR1 axis to sense alveolar hypoxia and promote peripheral vessel muscularization. These results have clinical significance in the development of novel therapeutics that target mechanisms of distal arterial remodeling associated with pulmonary hypertension induced by oxygen deficiency that is present in people living at high altitudes and patients with obstructive lung diseases.

Value of impedance cardiography in patients studied for pulmonary hypertension.

The aim of this study was to evaluate the accuracy and precision of impedance cardiography as a method for noninvasive hemodynamic evaluation of patients with pulmonary hypertension (PH). We performed a prospective and blinded study of patients who underwent right heart catheterization (RHC) for evaluation of known or presumed PH at the University of Florida from August 2009 to March 2010. The cohort consisted of a total of 39 patients (age = 57 ± 14 years, 87% women) with presumed (23%) or confirmed PH (77%) of different etiologies. Patients underwent RHC and impedance cardiography using the PhysioFlow PF-05. The PhysioFlow PF-05 measures cardiac output (CO) and LV end-diastolic volume (LVEDV), among other parameters. The median pulmonary artery pressure was 36 (IQR 26-56) mmHg. The CO (mean ± SD) by thermodilution (CO-T) and by impedance cardiography (CO-IC) was 5.9 ± 2.2 and 5.6 ± 1.5 L/min, respectively. Bland-Altman analysis of CO-T versus CO-IC revealed a mean of 0.3 L/min (95% LoA: -2.2 to +2.8). In patients with PH, the correlation of CO-T and CO-IC had a mean of 0.4 L/min (95% LoA: 2.9 and -2.2). Pulmonary artery occlusion pressure (PAOP) correlated with LVEDV (R (2) = 0.2, p = 0.005). By ROC analysis, EDV ≥ 200 ml had a sensitivity of 53% and a specificity of 86% for PAOP > 15 mmHg (AUC = 0.78). In patients with PH, impedance cardiography had good accuracy and fair precision for CO determination when compared with thermodilution. Impedance cardiography may provide information about the preload status and has the potential to become a cost-effective and noninvasive method for the follow-up of patients with PH.

Effect of balloon inflation volume on pulmonary artery occlusion pressure in patients with and without pulmonary hypertension.

BACKGROUND: Pulmonary artery occlusion pressure (PAOP) is used to differentiate patients with pulmonary hypertension (PH) associated with left-sided heart disease from other etiologies. Technical errors in the measurement of PAOP are common and lead to incorrect classification of the etiology of PH. We investigated the agreement among PAOP measurements obtained from both pulmonary arteries with balloon full (1.5 mL) and half (0.75 mL) inflation in patients undergoing right-sided heart catheterization for suspected PH. METHODS: Thirty-seven patients suspected or known to have PH who underwent right-sided heart catheterization were included. Seventy-six percent had PH (mean pulmonary arterial pressure > 25 mm Hg). The validity of the measurements was assessed by using five preestablished criteria based on hemodynamic, fluoroscopic, and gasometric data. For each patient, the measurement that most likely represented the left atrial pressure was labeled "best PAOP." RESULTS: Seventy percent of all the PAOP measurements met at least four of the five preestablished criteria for validity. In patients with PH (n = 28), the mean ± SE PAOP was 23.1 ± 2 and 19.1 ± 2 mm Hg for balloon full and half inflation, respectively, in the right pulmonary artery and 23.54 ± 2 and 19.07 ± 2 mm Hg for balloon full and half inflation, respectively, in the left pulmonary artery (P = .05). Bland-Altman analysis revealed lower bias and narrower limits of agreement with balloon half inflation. Wedge angiography showed that some balloon inflations failed to occlude upstream flow, whereas others had collateral vessels draining after the occlusion. CONCLUSIONS: PAOP can be falsely elevated in patients with PH according to the balloon inflation volume. Balloon half inflation was safe and correlated with higher precision and lower bias in the PAOP measurements.

Prevalence of pulmonary hypertension in end-stage cystic fibrosis and correlation with survival.

BACKGROUND: Limited information is available about the prevalence of pulmonary hypertension diagnosed by right heart catheterization (RHC) in patients with cystic fibrosis being evaluated for lung transplantation. It is unclear whether there are factors that can predict the presence of pulmonary hypertension and whether the presence of pulmonary hypertension influences patient outcomes. METHODS: The study included 57 unique and consecutive adult patients (33 women) with cystic fibrosis who underwent lung transplant evaluation at the University of Florida. RESULTS: The average age at evaluation was 31.8 +/- 10 years. All patients were in New York Heart Association class III. The median (interquartile range) of mean pulmonary artery pressure (PAP) was 26 (24-30) mm Hg. Thirty-six patients (63.2%) had pulmonary hypertension (mean PAP >or= 25 mm Hg) and had a significantly higher degree of hypoxemia and oxygen requirements. Echocardiography evidenced limitations for the diagnosis of pulmonary hypertension. The 5-year mortality rate was similar in patients with or without pulmonary hypertension; however, it was higher in 7 patients identified by cluster analysis and in patients with a left ventricular ejection fraction < 55%. CONCLUSIONS: More than half of our patients with cystic fibrosis and advanced lung disease have elevation of PAP, usually of mild degree. A lower left ventricular ejection fraction, but not the presence of pulmonary hypertension, was associated with worse outcomes.