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709: Influence of Intravenous Epoprostenol on the Transpulmonary Gradient of Vascular Endothelial Growth Factor (VEGF) in Patients with Pulmonary Arterial Hypertension
S312
Abstracts
poorer than in patients without that comorbid condition (p-values ranging from 0.020 to ⬍0.001). Conclusions: Patients with PAH but without the 7 common comorbidities tended to have significantly better FC (except systemic hypertension) and 6MWD than patients with any of these particular comorbid conditions. 708 REVEAL Registry: Comparison of Patients with ChildhoodOnset and Adult-Onset Pulmonary Vascular Disease Associated with Congenital Heart Disease R.J. Barst1, D. Ivy2, D.B. Badesch3, R.L. Benza4, C.G. Elliott5, H.W. Farber6, A.E. Frost7, A. Krichman8, T.G. Liou9, G.E. Raskob10, P. Wason11, K. Feldkircher11, A.J. Foreman12, M.D. McGoon13 1 Columbia University College of Physicians & Surgeons, New York, NY; 2University of Colorado Denver School of Medicine, The Children’s Hospital, Aurora, CO; 3University of Colorado Health Sciences Center, Aurora, CO; 4Allegheny General Hospital, Pittsburgh, PA; 5Intermountain Medical Center, Murray, UT; 6 Boston University School of Medicine, Boston, MA; 7Baylor College of Medicine, Houston, TX; 8Duke University Medical Center, Durham, NC; 9University of Utah, Salt Lake City, UT; 10 University of Oklahoma Health Sciences Center, Oklahoma City, OK; 11Actelion Pharmaceuticals US, Inc., South San Francisco, CA, 12 ICON Clinical Research, San Francisco, CA; 13Mayo Clinic, Rochester, MN Purpose: The Registry to EValuate Early And Long-term PAH Disease Management (REVEAL) is a multicenter, observational, U.S. study designed to assess demographic, clinical and management data on patients diagnosed with pulmonary arterial hypertension (PAH). Methods and Materials: All consenting PAH patients are being enrolled at ⬃50 sites in the US (25 sites are providing pediatric patients defined as ⱖ3 mos of age at time of diagnostic right heart catheterization). Enrollment data include: clinical and treatment history, physical examination, and disease severity assessment. Results: Of 2977 patients enrolled in the registry between March 2006 and September 2007, 342 patients have congenital heart disease (CHD) related PAH. Seventy-two patients have childhood-onset PAH [chPAH] (diagnosis ⱕ18 years) and 270 patients with CHD have adult-onset PAH [adPAH] (diagnosis ⱖ19 years). AdPAH-CHD had worse functional class (FC) at diagnosis compared with chPAH-CHD: adult: FC I, 7%; FC II, 30%; FC III, 58%; and FC IV, 6% vs pediatric: FC I, 3%; FC II, 56%; FC III, 31%; and FC IV, 11% (p⫽0.006 adult vs pediatric). AdPAH-CHD also had worse hemodynamics at PAH diagnosis compared with chPAH-CHD: PVRI 24 Wood units x m2 vs 15 Wood units x m2, respectively (p⫽0.002) and CI 2.7 L/min/m2 vs 3.7 L/min/m2, respectively (p⬍0.001). PAH treatment was started earlier after PAH diagnosis (median 2 mos vs 13 mos, respectively, p⬍0.001) in adPAH-CHD compared with chPAH-CHD. Finally, patients with adPAH-CHD were more likely to be treated with endothelin receptor antagonists compared with patients with chPAH-CHD (57% vs 43%, respectively, p⫽0.034); however, the use of phosphodiesterase 5 inhibitors and prostacyclin analogs was similar for both groups. Conclusions: Patients with AdPAH-CHD have worse hemodynamics and FC at PAH diagnosis compared with patients with chPAH-CHD, and appear to start treatment significantly earlier after PAH diagnosis than those with chPAH-CHD. 709 Influence of Intravenous Epoprostenol on the Transpulmonary Gradient of Vascular Endothelial Growth Factor (VEGF) in Patients with Pulmonary Arterial Hypertension
The Journal of Heart and Lung Transplantation February 2009
N. Selimovic, C.-H. Bergh, B. Andersson, E. Sakiniene, H. Carlsten, B. Rundqvist Sahlgrenska University Hospital, Gothenburg, Sweden; Sahlgrenska University Hospital, Gothenburg, Sweden Purpose: In patients with pulmonary arterial hypertension (PAH) the serum levels of VEGF have been found to be increased. The influence of intravenous epoprostenol on the transplumonary gradient of VEGF is unknown. The purpose was to prospectively measure serum levels during an acute epoprostenol challenge in PAH patients. Methods and Materials: Serum concentrations of VEGF were measured simultaneously in pulmonary artery (PA) and radial artery (RA) at baseline and during epoprostenol infusion (mean dosage 10⫾3 ng/kg/min) in PAH patients (idiopathic PAH, n⫽6; PAH associated with collagen vascular disease, n⫽13 and chronic thromboembolic pulmonary hypertension CTEPH, n⫽3) during right heart catheterization. Mean age was 57 years (range 26-76). Results: Baseline mean pulmonary artery pressure (mPAP) was 44⫾15 mm Hg (mean⫾SD) and pulmonary vascular resistance (PVR) was increased (8.4⫾4.1 WU). At baseline serum concentrations of VEGF were significantly higher in RA than in PA (p⬍0.001). During epoprostenol infusion the transpulmonary gradient of VEGF decreased significantly. Conclusions: A decreased transpulmonary gradient of VEGF during an acute epoprostenol intervention suggests that epoprostenol alters the pulmonary clearance and/or release of this growth factor. Increased concentrations of VEGF in the pulmonary artery at intervention indicate systemic interactions with epoprostenol. VEGF levels during epoprostenol infusion* Variables
Baseline, n ⴝ22
Epoprostenol, nⴝ22
p-value
VEGF RA , pg/ml VEGF PA , pg/ml ⌬VEGF/RA-PA),pg/ml RA/PA ratio mPAP , mm Hg** PVR, WU**
399(245-631) 189(119-334) 118 (46-297) 1.57 (1.11-2.79) 44 ⫾15 8.4⫾4.1
362(219-521) 287(187-437) 11 (-54-127) 1.03 (0.88-1.37) 42⫾13 6.7⫾4.1
0.29 0.02 0.004 0.002 0.36 ⬍0.001
*Data are presented as median (IQR – interquartile range) ** Data are presented as mean ⫾ SD
710 HIF-1␣ Activation by Cobalt Hyperpolarizes and Fragments Mitochondria in Pulmonary Artery Smooth Muscle Cells Creating a “Pulmonary Arterial Hypertension” Phenotype as Seen in Fawn-Hooded Rats P.T. Toth, H.J. Zhang, J. Rehman, Y. Zhang, S.L. Archer The University of Chicago, Chicago, IL Purpose: HIF-1␣ accumulates in the nucleus in the cultured pulmonary artery smooth muscle cells (PASMCs) of Fawn-hooded rats (FHR), a strain that spontaneously develops pulmonary arterial hypertension (PAH). The mitochondria in FHR PASMCs are fragmented and hyperpolarized, and we have previously shown that impaired mitochondrial function plays a critical role in the development and progression of PAH. However, the role of HIF-1␣ in this mitochondrial abnormality is unknown. Using cobalt chloride, a known activator of HIF-1␣, we compared the effects of HIF-1␣ activation in normal PASMCs and spontaneous HIF-1␣ activation in FHR PASMCs on the mitochondrial network. Methods and Materials: Smooth muscle cultures were established from pulmonary arteries of FHR and weight-matched control rats. HIF-1␣ nuclear accumulation was quantified by confocal microscopy using immunofluorescence. Mitochondrial network organization and mitochondrial membrane potential were assessed by confocal microscopy after staining with the mitochondria-specific, potentiometric
Abstracts
poorer than in patients without that comorbid condition (p-values ranging from 0.020 to ⬍0.001). Conclusions: Patients with PAH but without the 7 common comorbidities tended to have significantly better FC (except systemic hypertension) and 6MWD than patients with any of these particular comorbid conditions. 708 REVEAL Registry: Comparison of Patients with ChildhoodOnset and Adult-Onset Pulmonary Vascular Disease Associated with Congenital Heart Disease R.J. Barst1, D. Ivy2, D.B. Badesch3, R.L. Benza4, C.G. Elliott5, H.W. Farber6, A.E. Frost7, A. Krichman8, T.G. Liou9, G.E. Raskob10, P. Wason11, K. Feldkircher11, A.J. Foreman12, M.D. McGoon13 1 Columbia University College of Physicians & Surgeons, New York, NY; 2University of Colorado Denver School of Medicine, The Children’s Hospital, Aurora, CO; 3University of Colorado Health Sciences Center, Aurora, CO; 4Allegheny General Hospital, Pittsburgh, PA; 5Intermountain Medical Center, Murray, UT; 6 Boston University School of Medicine, Boston, MA; 7Baylor College of Medicine, Houston, TX; 8Duke University Medical Center, Durham, NC; 9University of Utah, Salt Lake City, UT; 10 University of Oklahoma Health Sciences Center, Oklahoma City, OK; 11Actelion Pharmaceuticals US, Inc., South San Francisco, CA, 12 ICON Clinical Research, San Francisco, CA; 13Mayo Clinic, Rochester, MN Purpose: The Registry to EValuate Early And Long-term PAH Disease Management (REVEAL) is a multicenter, observational, U.S. study designed to assess demographic, clinical and management data on patients diagnosed with pulmonary arterial hypertension (PAH). Methods and Materials: All consenting PAH patients are being enrolled at ⬃50 sites in the US (25 sites are providing pediatric patients defined as ⱖ3 mos of age at time of diagnostic right heart catheterization). Enrollment data include: clinical and treatment history, physical examination, and disease severity assessment. Results: Of 2977 patients enrolled in the registry between March 2006 and September 2007, 342 patients have congenital heart disease (CHD) related PAH. Seventy-two patients have childhood-onset PAH [chPAH] (diagnosis ⱕ18 years) and 270 patients with CHD have adult-onset PAH [adPAH] (diagnosis ⱖ19 years). AdPAH-CHD had worse functional class (FC) at diagnosis compared with chPAH-CHD: adult: FC I, 7%; FC II, 30%; FC III, 58%; and FC IV, 6% vs pediatric: FC I, 3%; FC II, 56%; FC III, 31%; and FC IV, 11% (p⫽0.006 adult vs pediatric). AdPAH-CHD also had worse hemodynamics at PAH diagnosis compared with chPAH-CHD: PVRI 24 Wood units x m2 vs 15 Wood units x m2, respectively (p⫽0.002) and CI 2.7 L/min/m2 vs 3.7 L/min/m2, respectively (p⬍0.001). PAH treatment was started earlier after PAH diagnosis (median 2 mos vs 13 mos, respectively, p⬍0.001) in adPAH-CHD compared with chPAH-CHD. Finally, patients with adPAH-CHD were more likely to be treated with endothelin receptor antagonists compared with patients with chPAH-CHD (57% vs 43%, respectively, p⫽0.034); however, the use of phosphodiesterase 5 inhibitors and prostacyclin analogs was similar for both groups. Conclusions: Patients with AdPAH-CHD have worse hemodynamics and FC at PAH diagnosis compared with patients with chPAH-CHD, and appear to start treatment significantly earlier after PAH diagnosis than those with chPAH-CHD. 709 Influence of Intravenous Epoprostenol on the Transpulmonary Gradient of Vascular Endothelial Growth Factor (VEGF) in Patients with Pulmonary Arterial Hypertension
The Journal of Heart and Lung Transplantation February 2009
N. Selimovic, C.-H. Bergh, B. Andersson, E. Sakiniene, H. Carlsten, B. Rundqvist Sahlgrenska University Hospital, Gothenburg, Sweden; Sahlgrenska University Hospital, Gothenburg, Sweden Purpose: In patients with pulmonary arterial hypertension (PAH) the serum levels of VEGF have been found to be increased. The influence of intravenous epoprostenol on the transplumonary gradient of VEGF is unknown. The purpose was to prospectively measure serum levels during an acute epoprostenol challenge in PAH patients. Methods and Materials: Serum concentrations of VEGF were measured simultaneously in pulmonary artery (PA) and radial artery (RA) at baseline and during epoprostenol infusion (mean dosage 10⫾3 ng/kg/min) in PAH patients (idiopathic PAH, n⫽6; PAH associated with collagen vascular disease, n⫽13 and chronic thromboembolic pulmonary hypertension CTEPH, n⫽3) during right heart catheterization. Mean age was 57 years (range 26-76). Results: Baseline mean pulmonary artery pressure (mPAP) was 44⫾15 mm Hg (mean⫾SD) and pulmonary vascular resistance (PVR) was increased (8.4⫾4.1 WU). At baseline serum concentrations of VEGF were significantly higher in RA than in PA (p⬍0.001). During epoprostenol infusion the transpulmonary gradient of VEGF decreased significantly. Conclusions: A decreased transpulmonary gradient of VEGF during an acute epoprostenol intervention suggests that epoprostenol alters the pulmonary clearance and/or release of this growth factor. Increased concentrations of VEGF in the pulmonary artery at intervention indicate systemic interactions with epoprostenol. VEGF levels during epoprostenol infusion* Variables
Baseline, n ⴝ22
Epoprostenol, nⴝ22
p-value
VEGF RA , pg/ml VEGF PA , pg/ml ⌬VEGF/RA-PA),pg/ml RA/PA ratio mPAP , mm Hg** PVR, WU**
399(245-631) 189(119-334) 118 (46-297) 1.57 (1.11-2.79) 44 ⫾15 8.4⫾4.1
362(219-521) 287(187-437) 11 (-54-127) 1.03 (0.88-1.37) 42⫾13 6.7⫾4.1
0.29 0.02 0.004 0.002 0.36 ⬍0.001
*Data are presented as median (IQR – interquartile range) ** Data are presented as mean ⫾ SD
710 HIF-1␣ Activation by Cobalt Hyperpolarizes and Fragments Mitochondria in Pulmonary Artery Smooth Muscle Cells Creating a “Pulmonary Arterial Hypertension” Phenotype as Seen in Fawn-Hooded Rats P.T. Toth, H.J. Zhang, J. Rehman, Y. Zhang, S.L. Archer The University of Chicago, Chicago, IL Purpose: HIF-1␣ accumulates in the nucleus in the cultured pulmonary artery smooth muscle cells (PASMCs) of Fawn-hooded rats (FHR), a strain that spontaneously develops pulmonary arterial hypertension (PAH). The mitochondria in FHR PASMCs are fragmented and hyperpolarized, and we have previously shown that impaired mitochondrial function plays a critical role in the development and progression of PAH. However, the role of HIF-1␣ in this mitochondrial abnormality is unknown. Using cobalt chloride, a known activator of HIF-1␣, we compared the effects of HIF-1␣ activation in normal PASMCs and spontaneous HIF-1␣ activation in FHR PASMCs on the mitochondrial network. Methods and Materials: Smooth muscle cultures were established from pulmonary arteries of FHR and weight-matched control rats. HIF-1␣ nuclear accumulation was quantified by confocal microscopy using immunofluorescence. Mitochondrial network organization and mitochondrial membrane potential were assessed by confocal microscopy after staining with the mitochondria-specific, potentiometric