February 2005

Pulmonary Arterial Hypertension

Scientific Updates – February 2005

Compiled by

United Therapeutics Corporation

In the journal scan this month there are a number of recent papers concerning various therapies and a few new papers on aspects of the basic pathobiology of PAH.

Ray Pediani - United Therapeutics

Braz J Med Biol Res. 2005 Feb;38(2):185-95. Epub 2005 Feb 15.

One-year follow-up of the effects of sildenafil on pulmonary arterial hypertension and veno-occlusive disease.

Barreto AC, Franchi SM, Castro CR, Lopes AA.

Departamento de Cardiologia Pediatrica e Cardiopatias Congenitas, Instituto do Coracao, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, SP, Brasil.

We hypothesized that chronic oral administration of the phosphodiesterase-5 inhibitor sildenafil could improve the exercise capacity and pulmonary hemodynamics in patients with pulmonary arterial hypertension (PAH) on the basis of previous short-term studies. We tested this hypothesis in 14 subjects with PAH, including seven patients with the idiopathic form and seven patients with atrial septal defects, but no other congenital heart abnormalities. Patients were subjected to a 6-min walk test and dyspnea was graded according to the Borg scale. Pulmonary flow and pressures were measured by Doppler echocardiography. Patients were given sildenafil, 75 mg orally three times a day, and followed up for 1 year. Sildenafil therapy resulted in the following changes: increase in the 6-min walk distance from a median value of 387 m (range 0 to 484 m) to 462 m (range 408 to 588 m; P < 0.01), improvement of the Borg dyspnea score from 4.0 (median value) to 3.0 (P < 0.01), and increased pulmonary flow (velocity-time integral) from a median value of 0.12 (range 0.08 to 0.25) to 0.23 (range 0.11 to 0.40; P < 0.01) with no changes in pulmonary pressures. In one patient with pulmonary veno-occlusive disease diagnosed by a lung biopsy, sildenafil had a better effect on the pulmonary wedge pressure than inhaled nitric oxide (15 and 29 mmHg, respectively, acute test). He walked 112 m at baseline and 408 m at one year. One patient died at 11 months of treatment. No other relevant events occurred. Thus, chronic administration of sildenafil improves the physical capacity of PAH patients and may be beneficial in selected cases of veno-occlusive disease.

Eur Respir J. 2005 Feb;25(2):244-9.

Survival with first-line bosentan in patients with primary pulmonary hypertension.

McLaughlin VV, Sitbon O, Badesch DB, Barst RJ, Black C, Galie N, Rainisio M, Simonneau G, Rubin LJ.

University of Michigan, 1500 East Medical Center Drive, Women's Hospital, Room L3119, Ann Arbor, MI, USA. vmclaugh@med.umich.edu

Primary pulmonary hypertension (PPH) is a progressive disease with high mortality. Administration of i.v. epoprostenol has demonstrated improved exercise tolerance, haemodynamics, and survival. The orally active, dual endothelin receptor antagonist bosentan improves exercise endurance, haemodynamics, and functional class over the short term. To determine the effect of first-line bosentan therapy on survival, this study followed 169 patients with PPH treated with bosentan in two placebo-controlled trials and their extensions. Data on survival and alternative treatments were collected from September 1999 (start of the first placebo-controlled study) to December 31, 2002. Observed survival up to 36 months was reported as Kaplan-Meier estimates and compared with predicted survival as determined for each patient by the National Institutes of Health Registry formula. Kaplan-Meier survival estimates were 96% at 12 months and 89% at 24 months. In contrast, predicted survival was 69% and 57%, respectively. In addition, at the end of 12 and 24 months, 85% and 70% of patients, respectively, remained alive and on bosentan monotherapy. Factors that predicted a worse outcome included World Health Organization Functional Class IV and 6-min walk distance below the median (358 m) at baseline. First-line bosentan therapy was found to improve survival in patients with advanced primary pulmonary hypertension.

Circ J. 2005 Feb;69(2):131-7.

Effects of the endothelin receptor antagonist bosentan on hemodynamics, symptoms and functional capacity in Japanese patients with severe pulmonary hypertension.

Sasayama S, Kunieda T, Tomoike H, Matsuzaki M, Shirato K, Kuriyama T, Izumi T, Origasa H, Giersbergen PL, Dingemanse J, Tanaka S.

Hamamatsu Rosai Hospital, Japan.

BACKGROUND: Endothelin (ET)-1 has a pathogenic role in pulmonary arterial hypertension (PAH). Recent clinical studies carried out in Western populations showed that blockade of the ET receptors by bosentan improves pulmonary hemodynamics and exercise capacity. In the present study, the efficacy of bosentan was assessed in Japanese patients with PAH. METHOD AND RESULTS: Because the pharmacokinetics of bosentan and its metabolites are similar in Japanese and Caucasian subjects, the same dose of bosentan, 125 mg twice daily, was administered in the Japanese open-label clinical trial. In 18 patients, mean pulmonary arterial pressure decreased from 52.4+/-13.8 to 46.8+/-13.8 mmHg (p=0.003) and cardiac index increased from 2.20+/-0.74 to 2.61 +/-0.72 L.min(-1).m(-2) (p=0.002). The 6-min walking distance increased from 410+/-89.5 to 494+/-86.0 m (p<0.0001). The dyspnea index (Borg scale) decreased from 3.2+/-2.4 to 2.2+/-1.7 (p=0.02). The specific activity scale (SAS) gradually increased throughout the study period from 2.9+/-0.8 to 4.6+/-1.9 METs (p=0.0005). WHO Class improved in 10 patients. CONCLUSION: Bosentan was well tolerated and improved the hemodynamics, symptoms, exercise capacity, and quality of life of Japanese patients with PAH. Thus, bosentan can be a valuable therapeutic option in Japanese patients.

Cardiovasc Res. 2005 Feb 15;65(3):751-61.

Continuous inhalation of carbon monoxide attenuates hypoxic pulmonary hypertension development presumably through activation of BKCa channels.

Dubuis E, Potier M, Wang R, Vandier C.

LABPART, Faculte de Medecine, 2 bis Boulevard Tonnelle, 37032 Tours, France. dubuis@liv.ac.uk

OBJECTIVE: We tested the hypothesis that inhalation of a low concentration of exogenous carbon monoxide (CO) attenuates the development of hypoxic pulmonary artery hypertension by activation of large-conductance voltage and Ca(2+)-activated K(+) channels (BK(Ca)). METHODS: The BK(Ca) activity was measured using whole-cell and inside-out patch clamp recordings in Wistar rat pulmonary artery (PA) myocytes. Pulmonary artery pressures were measured in vivo and membrane potentials were recorded in vitro in pressurized resistance arteries. RESULTS: Chronic CO inhalation slightly increases single-channel conductance of BK(Ca) channels and induces a large increase in the sensitivity of BK(Ca) channels to Ca(2+) of PA myocytes from normoxic and chronic hypoxic rats. Consequently, BK(Ca) currents are increased and play a more prominent role in controlling resting membrane potential of PA myocytes. Chronic CO inhalation also reduces hemodynamic changes induced by chronic hypoxia and attenuates hypoxic pulmonary artery hypertension. CONCLUSION: Chronic inhalation of CO attenuates hypoxic pulmonary artery hypertension development presumably through activation of BK(Ca) channels. These results highlight the potential use of CO as a novel avenue for research on the treatment of pulmonary artery hypertension (PAHT) in a similar manner to another gasotransmitter, nitric oxide.

Am J Cardiol. 2005 Feb 1;95(3):414-7.

Usefulness of latent left ventricular dysfunction assessed by Bowditch Treppe to predict stress-induced pulmonary hypertension in minimally symptomatic severe mitral regurgitation secondary to mitral valve prolapse.

Agricola E, Bombardini T, Oppizzi M, Margonato A, Pisani M, Melisurgo G, Picano E.

Division of Non-Invasive Cardiology, Cardiothoracic Department, San Raffaele Hospital, IRCCS, MilanoItaly.

We assessed whether the presence of latent myocardial dysfunction, evaluated by echocardiographic derived force-frequency relationship (FFR) during exercise, predicts the appearance of stress-induced pulmonary hypertension in minimally symptomatic patients with severe mitral regurgitation (MR). Two groups of patients were identified: group I with normal (</=40 mm Hg) and group II with abnormal (>40 mm Hg) peak stress systemic pulmonary artery pressure. Group I had normal and upsloping FFR and group II had abnormal flat or biphasic FFR. Therefore, in patients with severe MR and apparently normal left ventricular function, the stress-induced pulmonary hypertension seems to be related to the presence of latent left ventricular dysfunction.

Heart. 2005 Feb;91(2):142-5.

Pulmonary artery dissection: an emerging cardiovascular complication in surviving patients with chronic pulmonary hypertension.

Khattar RS, Fox DJ, Alty JE, Arora A.

Manchester Heart Centre, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, UK. rskhattar@hotmail.com

Pulmonary arterial dissection is an extremely rare and usually lethal complication of chronic pulmonary hypertension. The condition usually manifests as cardiogenic shock or sudden death and is therefore typically diagnosed at postmortem examination rather than during life. However, recent isolated reports have described pulmonary artery dissection in surviving patients. The first case of pulmonary artery dissection in a surviving patient with cor pulmonale caused by chronic obstructive pulmonary disease is presented. The aetiology, pathophysiology, and clinical presentation of pulmonary artery dissection are reviewed and factors that may aid diagnosis during life are discussed.

J Thorac Cardiovasc Surg. 2005 Feb;129(2):464-6.

Vasopressin to attenuate pulmonary hypertension and improve systemic blood pressure after correction of obstructed total anomalous pulmonary venous return.

Scheurer MA, Bradley SM, Atz AM.

Medical University of South Carolina, Charleston, USA. scheure@musc.edu

J Thorac Cardiovasc Surg. 2005 Feb;129(2):268-76.

Gene transfer of a TIE2 receptor antagonist prevents pulmonary hypertension in rodents.

Kido M, Du L, Sullivan CC, Deutsch R, Jamieson SW, Thistlethwaite PA.

Division of Cardiothoracic Surgery, University of California, San Diego 92103-8892, USA.

OBJECTIVES: Overexpression of angiopoietin 1 in the lung has been associated with human pulmonary hypertension. We hypothesized that inhibiting angiopoietin 1 signaling in the lung by administration of a receptor antagonist would block the development of pulmonary hypertensive vasculopathy in rodent models. METHODS: We injected 2 and 4 x 10(10) genomic particles of adeno-associated virus containing an extracellular fragment of the TIE2 receptor (AAV-sTIE2) into the pulmonary artery of 60 rats by using adeno-associated virus-lacZ and carrier-injected rats as control animals. Pulmonary hypertension was then induced by each of the following methods: (1) monocrotaline (group 1); (2) angiopoietin 1 expression in pulmonary vascular smooth muscle by adeno-associated virus gene transfer (group 2); or (3) oxygen deprivation (group 3). Animals were sacrificed at serial time points. At each time point, pulmonary artery pressures were measured, and pulmonary angiography was performed. Lungs were harvested for pathologic-molecular analysis. RESULTS: Each rodent pulmonary hypertension model demonstrated a significant increase in pulmonary artery pressures compared with that seen in control animals (P < .01). Administration of AAV-sTIE2 prevented pulmonary hypertension in the monocrotaline and angiopoietin 1 groups (from 44.6 +/- 2.1 to 18.8 +/- 1.9 mm Hg in the monocrotaline group and from 31.2 +/- 3.7 to 18.2 +/- 1.8 mm Hg in the angiopoietin 1 group, P < .001) but did not affect pulmonary hypertension in the hypoxia group. Pathologic analysis of group 1 and 2 lungs treated with AAV-sTIE2 demonstrated absence of smooth muscle cell proliferation within arterioles. Pulmonary angiography confirmed a lack of small pulmonary vessel occlusion in group 1 and 2 animals treated with AAV-sTIE2. CONCLUSIONS: Molecular blocking of the interaction between angiopoietin 1 and its endothelial receptor, TIE2, in the lung prevents pulmonary hypertension in 2 animal models of the disease. These experiments suggest a new strategy for understanding pulmonary hypertension based on the molecular biology of the pulmonary vascular wall.