Pulmonary Arterial Hypertension
Scientific Updates – June - Sept 2005
General diagnosis and treatment-related
publications:
Evaluation and management of the
patient with pulmonary arterial hypertension.
Ann Intern Med. 2005 Aug 16;143(4):282-92
Rubin LJ, Badesch DB.
University of California, San Diego, Medical Center, La Jolla, California
92037-7381, USA.
Increased pressure in the pulmonary circulation, or pulmonary hypertension, is
a common disorder that may complicate various cardiopulmonary conditions,
including severe obstructive airways disease and left ventricular dysfunction.
An increase in pulmonary arterial pressure that is not due to coexistent
cardiopulmonary disease, known as pulmonary arterial hypertension, may occur in
the absence of a demonstrable cause (idiopathic or familial); as a complication
of systemic conditions, such as connective tissue disease, HIV infection, or
chronic liver disease; or as a result of the use of fenfluramine anorexigens,
amphetamines, or cocaine. The development of disease-specific therapies for
pulmonary arterial hypertension over the past decade underscores the importance
of diagnosing pulmonary hypertension early in the course of the condition and
implementing a treatment strategy that is based on the condition's cause and
severity. In this review, the authors present approaches to the diagnosis and
management of pulmonary arterial hypertension, using a hypothetical case to
highlight the key management points.
Publication Types:
·
Case Reports
·
Review
·
Review, Tutorial
[HIV-Associated Pulmonary
Hypertension.]
[Article in German]
Herz. 2005 Sep;30(6):481-485
Friese G, Lohmeyer J, Seeger W, Grimminger F, Ghofrani HA.
Medizinische
Klinik II/V, Universitatsklinikum Giessen, Klinikstrasse 36, 35392, Giessen,
georg.friese@innere.med.uni-giessen.de.
Pulmonary
hypertension is a severe life-limitating disease often affecting younger
patients. The connection between HIV infection and the development of pulmonary
hypertension is well documented. The underlying pathobiology still remains
unclear. Given that the prognosis of HIV infection has been improved by highly
active antiretroviral therapy (HAART), severe pulmonary hypertension is
becoming a life-limiting factor.HIV patients suffering from exercise-induced
dyspnea should be tested for pulmonary hypertension, if other pulmonary or
cardiac disorders (e. g., restrictive or obstructive ventilation disorders,
pneumonia, coronary heart disease) can be excluded. The incidence of pulmonary
hypertension is 1,000 times higher in HIV patients as compared to the general
population. Estimated numbers of unreported cases are not included.A suspected
diagnosis of pulmonary hypertension can be substantiated by noninvasive
diagnostic methods (e. g., echocardiography), however, right heart catheterization
remains the diagnostic gold standard. As new therapeutic options with
prostanoids, endothelin antagonists, and phosphodiesterase-5 inhibitors are now
available, early and accurate diagnosis is essential.
Idiopathic pulmonary arterial
hypertension in children.
Curr Opin Pediatr. 2005 Jun;17(3):372-80
Rosenzweig EB,
Barst RJ.
Department of Pediatrics, Columbia University College
of Physicians & Surgeons, New York,
New York 10032,
USA.
PURPOSE OF REVIEW: Until recently, the diagnosis of idiopathic pulmonary
arterial hypertension was virtually a death sentence, particularly for
children. Although there is no cure for idiopathic pulmonary arterial
hypertension, recent medical advances have dramatically changed the course of
this disease in children. A review of some of the latest medical advances will
provide the reader with a better understanding of the most current treatment
options for children with idiopathic pulmonary arterial hypertension. RECENT
FINDINGS: The literature reviewed demonstrate sustained clinical and
hemodynamic improvement in children with various types of pulmonary arterial
hypertension as well as increased survival in patients with idiopathic
pulmonary arterial hypertension using current treatment strategies. SUMMARY:
This article will provide an overview of how the current diagnostic and
treatment strategies of idiopathic pulmonary arterial hypertension in children
have advanced over the last several years and how this impacts on clinical
practice.
Publication Types:
·
Review
·
Review, Tutorial
Pulmonary hypertension in congenital
heart disease.
Nurs Stand. 2005 Aug 24-30;19(50):41-9
Raja SG, Basu D.
Department of Paediatric Cardiac Surgery, Royal Hospital
for Sick Children, Glasgow. drrajashahzad@hotmail.com
Over the past 40 years, significant advances have been made in the diagnosis
and management of congenital heart defects. Improvements in diagnostic and
interventional cardiology, surgical technique, cardiopulmonary bypass and
post-operative intensive care have all contributed to a reduction in mortality
and morbidity. Despite these advances, pulmonary hypertension caused by
congenital heart defects remains a significant problem in the immediate
post-operative period, as well as long-term. This article reviews the
pathophysiology of pulmonary hypertension due to congenital heart disease and
discusses the options available for the management of this condition.
Links
Pulmonary hypertension in the newborn.
Greenough A, Khetriwal B.
Department of Child Health, Division of Asthma, Allergy and Lung Biology,
Guy's, King's, and St Thomas's School of Medicine, King's College London,
UK.
Pulmonary hypertension of the newborn occurs in 1.9 per 1000 live births
and affected infants are hypoxaemic because of right-to-left shunts through
the ductus arteriosus and foramen ovale. Pulmonary hypertension of the
newborn may be primary, or secondary to a variety of conditions including
intrapartum asphyxia, infection, pulmonary hypoplasia, congenital heart
disease or drug therapy. It may occur in association with a normal number
(maladaptation) or a decreased number of arteries (for example with
pulmonary hypoplasia). Few strategies used in infants with pulmonary
hypertension of the newborn have been subjected to rigorous evaluation.
Inhaled nitric oxide has been shown to reduce the need for extracorporeal
membrane oxygenation but not mortality, in term or near term born infants.
Preliminary evidence suggests that other vasodilators given by the inhaled
route may improve oxygenation and new vasodilators have become available;
appropriately designed trials with long-term outcomes are required to test
such therapies.
Links
Severe Pulmonary Hypertension during Pregnancy: Mode of Delivery and
Anesthetic Management of 15 Consecutive Cases.
Bonnin M, Mercier FJ, Sitbon O, Roger-Christoph S, Jais X, Humbert M,
Audibert F, Frydman R, Simonneau G, Benhamou D.
* Fellow, dagger Staff, daggerdagger Professor, Department of
Anesthesiology and Intensive Care, double dagger Staff, Professor,
Department of Pneumology and Intensive Care Unit, Pulmonary Vascular
Center, # Staff, ** Professor, Department of Obstetrics and Gynecology,
Antoine Beclere Hospital-Assistance Publique des Hopitaux de Paris (APHP).
BACKGROUND:: Available literature on pregnant women with severe pulmonary
hypertension (PH) relies mainly on anecdotal case reports and two series
only. METHODS:: The authors reviewed the charts of all pregnant women with
severe PH who were followed up at their institution during the past 10 yr,
to assess the multidisciplinary treatment and outcome of these patients.
RESULTS:: Fifteen pregnancies in 14 women with severe PH were managed
during this period: There were 4 cases of idiopathic pulmonary arterial
hypertension (PAH), 6 cases of congenital heart disease-associated PAH, 1
case of fenfluramine-associated PAH, 1 case of mixed connective
tissue-associated PAH, 1 case of human immunodeficiency virus-associated
PAH, and 2 cases of chronic thromboembolic PH. PH presented during
pregnancy in 3 patients. Two patients died before delivery at 12 and 23
weeks' gestation. Four patients had vaginal deliveries with regional
anesthesia: One died 3 months postpartum, one worsened, and two remained
stable. Four had cesarean deliveries during general anesthesia: One died 3
weeks postpartum, one worsened, and two remained stable. Five had cesarean
deliveries during low-dose combined spinal-epidural anesthesia: One died 1
week postpartum, and four remained stable. There were two fetal deaths: one
related to therapeutic abortion at 21 weeks' gestation and one stillbirth
at 36 weeks' gestation followed by the death of the mother 1 week later.
CONCLUSIONS:: Despite the most modern treatment efforts, the maternal
mortality was 36%. Scheduled cesarean delivery during combined spinal-epidural
anesthesia seemed to be an attractive approach, but there was no evidence
of actual benefit. Therefore, pregnancy must still be discouraged in
patients with severe PH.
J Pediatr. 2005 Jul;147(1):20-6
Comment in:
·
J
Pediatr. 2005 Jul;147(1):3-4.
Portopulmonary hypertension in pediatric patients.
Condino AA, Ivy DD, O'Connor JA, Narkewicz MR, Mengshol S, Whitworth JR, Claussen L, Doran A, Sokol RJ.
Section of Pediatric Gastroenterology, Hepatology & Nutrition, Department
of Pathology, The Children's Hospital, University
of Colorado Health Sciences Center, Denver, CO,
USA.
OBJECTIVES: To investigate the clinical presentation, manifestations, and
response to therapy of portopulmonary hypertension (PPHTN) in pediatric
patients. STUDY DESIGN: This study was a retrospective chart review describing
the evaluation and course of 7 patients with PPHTN. RESULTS: Causes of portal
hypertension (HTN) included biliary atresia (3 cases), cavernous transformation
of the portal vein (2 cases), and primary sclerosing cholangitis and
cryptogenic cirrhosis (1 case each). The median interval from the diagnosis of
portal HTN to PPHTN was 12.1 years. Four patients presented with a new heart
murmur, 4 presented with syncope, and 3 presented with dyspnea. Although
electrocardiograms (ECGs) and chest x-rays were normal in 3 and 2 patients,
respectively, echocardiograms diagnosed pulmonary HTN in all 7 patients. Five
patients had cardiac catheterizations; the average mean pulmonary artery
pressure was 65 +/- 20 mm Hg. Response to therapy was variable, and 4 patients
died. Postmortem lung tissue examination revealed plexiform lesions and
pulmonary arteriopathy. CONCLUSIONS: Because symptoms are subtle and may be
overlooked, pediatric patients with portal HTN who develop a new heart murmur,
dyspnea, syncope, or who are being evaluated for liver transplantation require
evaluation for PPHTN. ECG and chest x-ray are insensitive screens for PPHTN. An
echocardiogram and cardiology evaluation is essential for the diagnosis.
PDE-5 inhibitors
Sildenafil (Revatio) for pulmonary
arterial hypertension.
Med Lett Drugs Ther. 2005 Aug 15-29;47(1215-1216):65-7
[No authors listed]
A second oral alternative to more invasive therapy.
Antiproliferative effects of
phosphodiesterase type 5 inhibition in human pulmonary artery cells.
Am J Respir Crit Care Med. 2005 Jul 1;172(1):105-13
Wharton J, Strange JW, Moller GM, Growcott EJ, Ren X, Franklyn AP, Phillips SC, Wilkins MR.
Section on Experimental Medicine and Toxicology, Imperial
College London,
Hammersmith Campus, Du Cane Road, London W12 ONN,
UK.
j.wharton@imperial.ac.uk
RATIONALE: Phosphodiesterase Type 5 (PDE5) inhibition represents a novel strategy
for the treatment of pulmonary hypertension. OBJECTIVES: Our aim was to
establish the distribution of PDE5 in the pulmonary vasculature and effects of
PDE5 inhibition on pulmonary artery smooth muscle cells (PASMCs). METHODS AND
MEASUREMENTS: PDE5 expression was examined by immunohistochemistry and Western
blotting, in both normal and hypertensive lung tissues. DNA synthesis,
proliferation, PDE activity, and apoptosis were measured in distal human PASMCs
treated with soluble guanylyl cyclase activators (nitric oxide donors and
BAY41-2272) and sildenafil. MAIN RESULTS: Cells containing PDE5 and
alpha-smooth muscle actin occurred throughout the pulmonary vasculature,
including obstructive intimal lesions. Three molecular forms of PDE5 were
identified and protein expression was greater in hypertensive than control lung
tissue. Most cyclic guanosine monophosphate hydrolysis (about 80%) in cultured
cells was attributed to PDE5. Sildenafil induced a greater elevation of
intracellular cyclic guanosine monophosphate levels compared with nitric oxide
donors and BAY41-2272 (about 10-fold versus about 2-fold) and cotreatment had a
synergistic effect, increasing cyclic nucleotide levels up to 50-fold. Dual
stimulation of soluble guanylyl cyclase and inhibition of PDE5 activities also
had significant downstream effects, increasing phosphorylation of
vasodilator-stimulated phosphoprotein, reducing DNA synthesis and cell
proliferation, and stimulating apoptosis, and these effects were mimicked by
cyclic guanosine monophosphate analogs. CONCLUSIONS: Phosphodiesterase Type 5
is the main factor regulating cyclic guanosine monophosphate hydrolysis and
downstream signaling in human PASMCs. The antiproliferative effects of this
signaling pathway may be significant in the chronic treatment of pulmonary
hypertension with PDE5 inhibitors such as sildenafil.
Links
Is sildenafil effective in secondary pulmonary hypertension due to
systemic lupus erythematosus? A case report.
Hanta I, Demir M, Akpinar O,
Kocabas A,
Ozbek S.
Department of Chest Medicine, Cukurova
University, School
of Medicine, Adana,
Balcali, 01330, Turkey,
ihanta@cu.edu.tr.
![Text Box: Clin Rheumatol. 2005 Jun 11; [Epub ahead of print] Related Articles, Links
Is sildenafil effective in secondary pulmonary hypertension due to systemic lupus erythematosus? A case report.
Hanta I, Demir M, Akpinar O, Kocabas A, Ozbek S.
Department of Chest Medicine, Cukurova University, School of Medicine, Adana, Balcali, 01330, Turkey, ihanta@cu.edu.tr.](0506_09_files/image009.gif)
Links
Pulmonary hypertension: inhaled nitric oxide, sildenafil and natriuretic
peptides.
Steiner MK, Preston IR, Klinger JR, Hill NS.
Pulmonary, Critical Care and Sleep Divisions, Tufts-New
England Medical
Center, Boston,
Massachussets, USA.
Phosphodiesterase-5 (PDE5) inhibitors and other agents that modulate
intracellular cGMP are now emerging as promising, safe, and easy to
administer therapies for pulmonary hypertension, with relatively few side
effects. Recent studies have shown that PDE5 inhibitors are potent acute
pulmonary vasodilators in experimental models that partially reverse
established pulmonary arterial hypertension and blunt chronic pulmonary
hypertension. In addition, studies on animals reveal that PDE5 inhibitors
work in concert with nitric oxide and/or natriuretic peptide levels by
enhancing intracellular cGMP and cGMP-mediated vasodilator effects.
Further, the combination of PDE5 inhibitors and agents that increase cGMP
or cAMP also yields additive beneficial effects on pulmonary hemodynamics
in patients with pulmonary arterial hypertension.
ERAs
J Am Coll Cardiol. 2005 Aug
16;46(4):697-704
Comment in:
·
J
Am Coll Cardiol. 2005 Aug 16;46(4):705-6.
Effects of long-term bosentan in
children with pulmonary arterial hypertension.
Rosenzweig EB,
Ivy DD, Widlitz A, Doran A, Claussen LR, Yung D, Abman SH, Morganti A, Nguyen N, Barst RJ.
Division of Pediatric Cardiology, New York
Presbyterian Hospital, New York,
New York 10032,
USA.
esb14@columbia.edu
OBJECTIVES: This study investigated the long-term outcome of children with
pulmonary arterial hypertension (PAH) treated with bosentan therapy, with or
without concomitant prostanoid therapy. BACKGROUND: Bosentan, an oral
endothelin ET(A)/ET(B) receptor antagonist, improves hemodynamics and exercise
capacity in adults with PAH; however, limited data are available on its
long-term effects in children. METHODS: In this retrospective study, 86
children with PAH (idiopathic, associated with congenital heart or connective
tissue disease) started bosentan with or without concomitant intravenous
epoprostenol or subcutaneous treprostinil therapy. Hemodynamics, World Health
Organization (WHO) functional class, and safety data were collected. RESULTS:
At the cutoff date, 68 patients (79%) were still treated with bosentan, 13
(15%) were discontinued, and 5 (6%) had died. Median exposure to bosentan was
14 months. In 90% of the patients (n = 78), WHO functional class improved (46%)
or was unchanged (44%) with bosentan treatment. Mean pulmonary artery pressure
and pulmonary vascular resistance decreased (64 +/- 3 mm Hg to 57 +/- 3 mm Hg,
p = 0.005 and 20 +/- 2 U x m2 to 15 +/- 2 U x m2, p = 0.01, respectively; n =
49). Kaplan-Meier survival estimates at one and two years were 98% and 91%,
respectively. The risk for worsening PAH was lower in patients in WHO
functional class I/II at bosentan initiation than in patients in WHO class
III/IV at bosentan initiation. CONCLUSIONS: These data suggest that bosentan,
an oral endothelin ET(A)/ET(B) receptor antagonist, with or without concomitant
prostanoid therapy, is safe and efficacious for the treatment of PAH in
children.
Links
Severe left ventricular dysfunction secondary to primary pulmonary
hypertension: bridging therapy with bosentan before lung transplantation.
Brauchlin AE, Soccal PM, Rochat T, Spiliopoulos A, Nicod LP, Trindade PT.
Division
of Pneumology, University Hospital
of Geneva, Geneva, Switzerland.
When right ventricular failure develops secondary to primary pulmonary
hypertension, right-left ventricular interaction may lead to severe
impairment of left ventricular function. In such cases, many experts favor
combined heart-lung transplantation by fear that the left ventricle may not
recover after transplantation of the lungs alone. We report a case of
primary pulmonary hypertension with severely diminished right and left
ventricular function. The patient was rendered amenable to isolated
pulmonary transplantation with the endothelin-receptor antagonist bosentan.
The medication improved right and left ventricular function to the point
that heart transplantation no longer appeared necessary. After double-lung
transplantation the patient's cardiac function made a full recovery. This
approach might be particularly welcome considering both the current donor
organ shortage and the limited number of surgical teams with expertise in
heart-lung transplantation.
Ambrisentan therapy for pulmonary
arterial hypertension.
J Am Coll Cardiol. 2005 Aug 2;46(3):529-35
Galie N, Badesch D, Oudiz R, Simonneau G, McGoon MD, Keogh AM, Frost AE, Zwicke D, Naeije R, Shapiro S, Olschewski H, Rubin LJ.
University of Bologna,
Bologna, Italy. n.galie@bo.nettuno.it
OBJECTIVES: The purpose of this study was to examine the efficacy and safety of
four doses of ambrisentan, an oral endothelin type A receptor-selective
antagonist, in patients with pulmonary arterial hypertension (PAH). BACKGROUND:
Pulmonary arterial hypertension is a life-threatening and progressive disease
with limited treatment options. Endothelin is a vasoconstrictor and smooth
muscle cell mitogen that plays a critical role in the pathogenesis and
progression of PAH. METHODS: In this double-blind, dose-ranging study, 64
patients with idiopathic PAH or PAH associated with collagen vascular disease,
anorexigen use, or human immunodeficiency virus infection were randomized to
receive 1, 2.5, 5, or 10 mg of ambrisentan once daily for 12 weeks followed by
12 weeks of open-label ambrisentan. The primary end point was an improvement
from baseline in 6-min walk distance (6MWD); secondary end points included Borg
dyspnea index, World Health Organization (WHO) functional class, a subject global
assessment, and cardiopulmonary hemodynamics. RESULTS: At 12 weeks, ambrisentan
increased 6MWD (+36.1 m, p < 0.0001) with similar and statistically
significant increases for each dose group (range, +33.9 to +38.1 m).
Improvements were also observed in Borg dyspnea index, WHO functional class,
subject global assessment, mean pulmonary arterial pressure (-5.2 mm Hg, p <
0.0001), and cardiac index (+0.33 l/min/m2, p < 0.0008). Adverse events were
mild and unrelated to dose, including the incidence of elevated serum
aminotransferase concentrations >3 times the upper limit of normal (3.1%).
CONCLUSIONS: Ambrisentan appears to improve exercise capacity, symptoms, and
hemodynamics in patients with PAH. The incidence and severity of liver enzyme
abnormalities appear to be low.
Publication Types:
·
Clinical Trial
·
Randomized Controlled Trial
Links
Endothelin antagonism in pulmonary hypertension, heart failure, and
beyond.
Attina T, Camidge R, Newby DE, Webb DJ.
Clinical Research Centre, Department of Medical Sciences, University of Edinburgh,
Edinburgh, UK.
Prostanoids
Transition from Intravenous
Epoprostenol to Intravenous Treprostinil in Pulmonary Hypertension.
Am J Respir Crit Care Med. 2005 Sep 8
Gomberg-Maitland M,
Tapson VF, Benza RL, McLaughlin VV,
Krichman A, Widlitz AC, Barst RJ.
Department of Cardiology, The University
of Chicago Hospitals, Chicago, Illinois,
USA.
Rationale: Intravenous epoprostenol improves exercise capacity and survival in
pulmonary arterial hypertension patients. The prostacyclin analogue
treprostinil is also efficacious by subcutaneous infusion, is easier to
administer, and has a longer half-life. With recent demonstration of
bioequivalence between subcutaneous and intravenous treprostinil, intravenous
treprostinil may have an overall better risk-benefit profile than intravenous
epoprostenol. Objective: To evaluate the safety and efficacy of transitioning
pulmonary arterial hypertension patients from intravenous epoprostenol to
intravenous treprostinil. Methods: Patients enrolled in a 12 week prospective
open label study were switched from intravenous epoprostenol to intravenous
treprostinil over 24-48 hours. The intravenous treprostinil dose was adjusted
to minimize symptoms/side effects. Results: 31 patients (mean age 43 yrs; 22
women) were enrolled. 27 patients completed the protocol; four patients
transitioned back to epoprostenol. Six-minute walk distance (n=27; baseline:
438+/-16m; week 12: 439 +/-16m), Naughton-Balke treadmill test time (n=26;
baseline:658+/-75 sec; week 12: 707+/-54 sec), functional class, and Borg score
were maintained with intravenous treprostinil at week 12 vs. intravenous
epoprostenol before transition. At week 12, mean pulmonary artery pressure
increased 4 +/- 1 mmHg (n=27, p <0.01), cardiac index decreased 0.4 +/- 0.1
L/m/m(2)(n=27,p= 0.01), and pulmonary vascular resistance increased 3 +/- 1
Wood units/m(2) (n=26, p < 0.01). No serious adverse events were attributed
to treprostinil. Conclusions: These data suggest that transition from intravenous
epoprostenol to intravenous treprostinil is safe and effective; whether the
hemodynamic differences of intravenous treprostinil are clinically important
requires longe