Conference Abstracts
BASIC SCIENCE: Loss of apelin signaling impairs nitric oxide synthesis and exacerbates pulmonary hypertension
Hyung Chun, MD
We have previously shown that monocrotaline (MCT)-induced pulmonary hypertension (PH) is associated with an early and progressive IL-6 mRNA upregulation, IL-6 bioactivity, loss of endothelial caveolin-1 and reciprocal PY-STAT3 activation. PY-STAT3 is activated by IL-6, and caveolin-1 suppresses PY-STAT3 activation. Caveolin-1, an important immunomodulator, inhibits cell proliferation and participates in apoptosis. Anti-inflammatory treatment instituted early inhibits IL-6 upregulation, rescues caveolin-1, inhibits PY-STAT3 activation and attenuates PH. Our main purpose was to investigate whether inflammation played any role in hypoxia-induced PH in rats and to compare and contrast with the MCT model.
Male Sprague-Dawley rats (150-175 g) were subjected to hypobaric (1/2 atmospheric) hypoxia or given a single sc injection of MCT (60 mg/kg). Hemodynamic data, the expression of caveolin-1and PY-STAT3 in the lungs were examined at 48h, 1 and 2 wks.
PH and RVH were observed at 2 wks post-MCT and at 1and 2 wks of hypoxia. PY-STAT3 activation occurred in both models before the onset of PH and was progressive. The MCT model revealed progressive loss of caveolin-1; whereas in the hypoxia model, caveolin-1 expression was not altered.
MCT-induced PH is associated with disruption of endothelial caveolin-1 and reciprocal activation of PY-STAT3. In contrast, the hypoxia model exhibited PY-STAT3 activation without concomitant loss of caveolin-1. Importantly, these dissimilar models of PH show hyper-activation of PY-STAT3 before the onset of PH, indicating a role of inflammatory response to injury in the pathogenesis of PH. Since caveolin-1 suppresses PY-STAT3 activation; the significant PY-STAT3 activation in the hypoxia model may be indicative of caveolin-1 dysfunction. Thus, the disruption or dysfunction of endothelial caveolin-1 may promote inflammatory response and cell proliferation, contributing to PH.
Reports to date have suggested that pericardial effusion is an uncommon and unfavorable sign in patients with Pulmonary Arterial Hypertension. The long-term significance of effusion size and patient characteristics remains unclear and the safety of pericardiocentesis in this patient population has been questioned.
Single center cohort study of all patients first seen with Group 1 PAH at a specialty PH center between 1995 and 2006. All patients had echocardiograms. Pericardiocentesis was performed under echocardiographic guidance with moderate conscious sedation in a monitored inpatient setting for those who received intervention.
Of 577 patients, 26% (150 patients) had pericardial effusion on echocardiography. The majority of effusions (128 of 150) were small (<1 cm in size). Moderate or greater effusions were present in 22 patients (9.3%) with evidence of hemodynamic compromise in 14 patients requiring pericardiocentesis. After adjusting for age, sex, functional class, and six minute walk distance, two factors independently associated with the presence of pericardial effusion were collagen vascular disease (OR 3.71; 2.05, 6.87) and right atrial pressure (OR 1.83 per 5 mm Hg; 1.33, 2.54). Median survival for patients with ≥ moderate effusion, mild effusion, and no effusion was 12 months, 36 months, and 69 months respectively (p<0.001). The degree of the pericardial effusion was most predictive of poor outcome in patients with collagen vascular disease associated PAH. Twelve of 14 patients undergoing pericardiocentesis had collagen vascular disease. Treated pericardial effusions were large (832 ± 512) and generally serous. Survival at 48 hours was 100% and associated with clinical improvement in 13/14. Repeat pericardiocentesis was required in three patients.
The incidence of any pericardial effusion on echocardiogram is low in patients with PAH. Effusions are typically small, occur in the setting of connective tissue disease, and are associated with elevated right atrial pressure. However, even small pericardial effusions are independently associated with poor survival. Rarely do pericardial effusions cause tamponade but when present can be safely drained with echo-guided pericardiocentesis in a monitored inpatient setting.
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