Pulmonary vascular morphology as an imaging biomarker in chronic thromboembolic pulmonary hypertension.

Patients with chronic thromboembolic pulmonary hypertension (CTEPH) have morphologic changes to the pulmonary vasculature. These include pruning of the distal vessels, dilation of the proximal vessels, and increased vascular tortuosity. Advances in image processing and computer vision enable objective detection and quantification of these processes in clinically acquired computed tomographic (CT) scans. Three-dimensional reconstructions of the pulmonary vasculature were created from the CT angiograms of 18 patients with CTEPH diagnosed using imaging and hemodynamics as well as 15 control patients referred to our Dyspnea Clinic and found to have no evidence of pulmonary vascular disease. Compared to controls, CTEPH patients exhibited greater pruning of the distal vasculature (median density of small-vessel volume: 2.7 [interquartile range (IQR): 2.5-3.0] vs. 3.2 [3.0-3.8]; P = 0.008), greater dilation of proximal arteries (median fraction of blood in large arteries: 0.35 [IQR: 0.30-0.41] vs. 0.23 [0.21-0.31]; P = 0.0005), and increased tortuosity in the pulmonary arterial tree (median: 4.92% [IQR: 4.85%-5.21%] vs. 4.63% [4.39%-4.92%]; P = 0.004). CTEPH was not associated with dilation of proximal veins or increased tortuosity in the venous system. Distal pruning of the vasculature was correlated with the cardiac index (R = 0.51, P = 0.04). Quantitative models derived from CT scans can be used to measure changes in vascular morphology previously described subjectively in CTEPH. These measurements are also correlated with invasive metrics of pulmonary hemodynamics, suggesting that they may be used to assess disease severity. Further work in a larger cohort may enable the use of such measures as a biomarker for diagnostic, phenotyping, and prognostic purposes.

Pulmonary function test abnormalities in pulmonary vascular disease and chronic heart failure.

Diagnostic criteria based on pulmonary function testing for pulmonary vascular disease and CHF are imprecise. Although these tests constitute a necessary part of the work-up of a patient with dyspnea, additional studies are required to obtain a final diagnosis in the setting of cardiopulmonary vascular disease. In contrast, specific pulmonary function tests may offer an objective means of assessing severity of dysfunction resulting from pulmonary hypertension or CHE Serial measurements of pulmonary function offer insight into general and specific patterns of cardiopulmonary vascular disease and are useful in evaluating response to treatment.

IL-13 stimulates vascular endothelial cell growth factor and protects against hyperoxic acute lung injury.

Hyperoxia is an important cause of acute lung injury. To determine whether IL-13 is protective in hyperoxia, we compared the survival in 100% O(2) of transgenic mice that overexpress IL-13 in the lung and of nontransgenic littermate controls. IL-13 enhanced survival in 100% O(2). One hundred percent of nontransgenic mice died in 4-5 days, whereas 100% of IL-13-overexpressing mice lived for more than 7 days, and many lived 10-14 days. IL-13 also stimulated VEGF accumulation in mice breathing room air, and it interacted with 100% (2) to increase VEGF accumulation further. The 164-amino acid isoform was the major VEGF moiety in bronchoalveolar lavage from transgenic mice in room air, whereas the 120- and 188-amino acid isoforms accumulated in these mice during hyperoxia. In addition, antibody neutralization of VEGF decreased the survival of IL-13-overexpressing mice in 100% (2). These studies demonstrate that IL-13 has protective effects in hyperoxic acute lung injury. They also demonstrate that IL-13, alone and in combination with 100% (2), stimulates pulmonary VEGF accumulation, that this stimulation is isoform-specific, and that the protective effects of IL-13 are mediated, in part, by VEGF.

Interleukin-6-induced protection in hyperoxic acute lung injury.

Hyperoxic lung injury is commonly encountered in patients who require treatment with high concentrations of inspired oxygen. To determine whether interleukin (IL)-6 is protective in oxygen toxicity, we compared the effects of 100% O(2) in transgenic mice that overexpress IL-6 in the lung and transgene (-) controls. IL-6 markedly enhanced survival, with 100% of transgene (-) animals dying within 72 to 96 h, 100% of transgene (+) animals living for more than 8 d and more than 90% of transgene (+) animals living longer than 12 d. This protection was associated with markedly diminished alveolar-capillary protein leak, endothelial and epithelial membrane injury, and lung lipid peroxidation. Hyperoxia also caused cell death with DNA fragmentation in the lungs of transgene (-) animals and IL-6 markedly diminished this cytopathic response. The protective effects of IL-6 were not associated with significant alterations in the activities of copper/ zinc superoxide dismutase (SOD) or manganese SOD. They were, however, associated with the enhanced accumulation of the cell-death inhibitor Bcl-2, but not the cell-death stimulator BAX, and with the heightened accumulation of the cell-death regulator tissue inhibitor of metalloproteinase-1 (TIMP-1). These studies demonstrate that IL-6 markedly diminishes hyperoxic lung injury and that this protection is associated with a marked diminution in hyperoxia-induced cell death and DNA fragmentation. They also demonstrate that this protection is not associated with significant alterations in SOD activity, but is associated with the induction of Bcl-2 and TIMP-1.

Targeted lung expression of interleukin-11 enhances murine tolerance of 100% oxygen and diminishes hyperoxia-induced DNA fragmentation.

Acute lung injury is a frequent and treatment-limiting consequence of therapy with hyperoxic gas mixtures. To determine if IL-11 is protective in oxygen toxicity, we compared the effects of 100% O2 on transgenic mice that overexpress IL-11 in the lung and transgene (-) controls. IL-11 markedly enhanced survival in 100% O2 with 100% of transgene (-) animals dying within 72-96 h and > 90% of transgene (+) animals surviving for more than 10 d. This protection was associated with markedly diminished alveolar-capillary protein leak, endothelial and epithelial membrane injury, lipid peroxidation, and pulmonary neutrophil recruitment. Significant differences in copper zinc superoxide dismutase and catalase activities were not noted and the levels of total, reduced and oxidized glutathione were similar in transgene (+) and (-) animals. Glutathione reductase, glutathione peroxidase, and manganese superoxide dismutase activities were slightly higher in transgene (+) as versus (-) mice after 100% O2 exposure, and IL-11 diminished hyperoxia-induced expression of IL-1 and TNF. Hyperoxia also caused cell death with DNA fragmentation in the lungs of transgene (-) animals and IL-11 markedly diminished this cell death response. These studies demonstrate that IL-11 markedly diminishes hyperoxic lung injury. They also demonstrate this protection is associated with small changes in lung antioxidants, diminished hyperoxia-induced IL-1 and TNF production, and markedly suppressed hyperoxia-induced DNA fragmentation.

Electromechanical dissociation following verapamil and propranolol ingestion: a physiologic profile.

We present a case of combined verapamil and propranolol ingestion in a young woman with a DDD pacer from whom hemodynamic, echocardiographic, and toxicologic data were obtained simultaneously. Analysis of the data from these combined sources suggests a progression of (1) recovery of myocardial contractility, (2) return of systemic vascular resistance, and (3) return of intrinsic electrical activity of the heart. That contractility returns before intrinsic electrical activity strongly for the early use of transvenous temporary pacing wires. Furthermore, our patient's complete recovery after a prolonged electromechanical dissociation arrest would again argue for very aggressive resuscitation efforts in this setting.

Cytomegalovirus as a primary pulmonary pathogen in AIDS.

In patients with AIDS, isolation of cytomegalovirus (CMV) from respiratory secretions is common. It is often found with other pathogens, which has led to debate regarding its role as a primary pulmonary pathogen. A retrospective investigation of patients with AIDS and CMV as a sole pulmonary isolate was performed in an attempt to describe their clinical presentation and course. All patients admitted to the hospital with pneumonia and with BAL or transbronchial biopsy (TBB) specimen positive for CMV between 1991 and 1994 were identified through a review of inpatient records. Inclusion criteria included positive CMV cultures from BAL, cytomegalic inclusion bodies from BAL or TBB, and thorough documentation of the absence of other pulmonary pathogens. Nine patients met the inclusion criteria for CMV pneumonitis. Seven were male and two were female, ages 26 to 44 years, and all had a history of opportunistic infections. Typical clinical presentation was characterized by increased respiratory rate, hypoxemia, and diffuse interstitial infiltrates. The mean CD4 count was 29.6 (+/- 22) cells per cubic millimeter, mean lactate dehydrogenase level was 414 (+/- 301) IU/L, and in seven patients in whom CMV antigen was measured it was greater than 50 positive cells per 200,000 WBCs. Three untreated patients died of respiratory failure and three had autopsy confirmation of CMV pneumonia. Five patients were treated with anti-CMV therapy for at least 2 weeks, and all demonstrated improvement in symptoms, oxygen saturation, and chest radiograph. At 3 months follow-up, all five patients were asymptomatic with no pulmonary symptoms. At 6 months follow-up, three of the five patients remained asymptomatic; the other two died of other opportunistic infections. In at least these nine patients, CMV represented a primary pulmonary pathogen. Patients who were treated responded quickly and were able to be discharged home from the hospital with marked improvement in their symptoms. We recommend that clinicians consider this diagnosis in the proper setting and consider treatment with anti-CMV therapy.