|TABLE OF CONTENTS
The Pathology of Pulmonary
Pathobiology of Pulmonary Hypertension
Risk Factors and Associated Conditions for Pulmonary
Genetics of Pulmonary Hypertension
Diagnosis and Assessment of Pulmonary Hypertension
Medical Therapy of Pulmonary Hypertension
Atrial Septostomy for Pulmonary Hypertension
Transplantation for Pulmonary Hypertension
Nomenclature and Classification of Pulmonary Hypertension
Primary pulmonary hypertension is a rare condition,
with an estimated prevalence of 1-2 per million people. Because the symptoms of PPH are
nonspecific, and the physical findings can be subtle, the disease is often diagnosed in
its later stages. The natural history of PPH is usually progressive and fatal.
In 1973, the World Health Organization sponsored an international meeting on primary
pulmonary hypertension, spurned by the interest created by the sudden increase in patients
with PPH who had used the anorexigen, aminorex fumarate. At that vanguard meeting,
international experts reviewed and discussed the pathology, pathophysiology, epidemiology,
and clinical features of PPH. The meeting also focused on defining areas of future
research with the goal of providing a better understanding of the cause and discovering
effective treatments for PPH.
The past 25 years has witnessed remarkable progress in the field of pulmonary
hypertension. The pathology is now better defined and intricate pathobiologic mechanisms
are becoming unfolded that explain many of the enigmatic features of PPH. Risk factors
have been identified, and the genetics are being characterized. Advances in technology
allow a better diagnosis and assessment of the disease severity. Important therapies are
now available that have been shown to improve quality of life and survival.
On the 25th anniversary of this first meeting, clinical scientists from around the
world gathered again to review and discuss the features of PPH, as well as the field of
pulmonary arterial hypertension. Ironically, a recent epidemic of PPH associated with a
new class of anorexigens has again heightened world interest. Like before, the merging of
a variety of disciplines provided an opportunity for discussion and debate, leading to a
better understanding of the pathology, pathobiology, risk factors, genetics, diagnosis and
treatment of the disease. New drugs, such as epoprostenol, and surgical therapies, such as
heart-lung transplant that were unavailable 25 years ago, are having an important impact
on the prognosis.
This executive summary highlights key features of PPH and represents a consensus of the
participants who contributed to this working meeting. It provides insights into our
current understanding of PPH, with specific recommendations for current practice and
future directions for research.
Stuart Rich, MD - Chair Rush Medical College (Chicago, USA)
Lewis J. Rubin, MD Co-Chair University of Maryland (Baltimore, USA)
Lucien Abenhaim, MD McGill University (Montreal, Canada)
Robyn J. Barst, MD Columbia University (New York, USA)
Bruce H. Brundage, MD UCLA School of Medicine (Los Angeles, USA)
Alfred P. Fishman, MD University of Pennsylvania (Philadelphia, USA)
Prof. Sheila G. Haworth University of London (London, UK)
Prof. Timothy Higenbottam The University of Sheffield Medical School (Sheffield, UK)
David Langleben, MD McGill University (Montreal, Canada)
Michael D. McGoon, MD Mayo Clinic (Rochester, MN USA)
Prof. Robert Naeije Erasme Hospital (Brussels, Belgium)
John H. Newman, MD Vanderbilt University (Nashville, USA)
Marlene Rabinovitch, MD The Hospital for Sick Children (Toronto, Canada)
Julio Sandoval, MD Instituto Nacional de Cardiologia (Mexico City, Mexico)
Prof. Gerald Simonneau Hospital Antoine-Beclere (Clamart, France)
Norbert F. Voelkel, MD University of Colorado Health Sciences Center (Denver, USA)
The Pathology of
The pathology of the pulmonary vascular bed in
pulmonary hypertension remains central to our understanding of clinical observations and
pathobiologic mechanisms. The cellular and molecular features of the pathology continues
to influence the clinical appraisal of the disease.
The endothelium presents a challenge to the
pathologist because of the marked heterogeneity in the endothelium of the pulmonary
vascular bed. In addition, the relationship between the phenotype and function of the
endothelial cell is not fully understood. There may also be discordance between the
patient age and the apparent cell age of the endothelium.
The characteristics of the disease and the vulnerability of different phenotypes to a
variety of insults may determine the nature and severity of endothelial changes that are
observed. This makes our understanding of how modulating the chemical and physical
environment alters the endothelium quite important. Immunocytochemistry and in situ
hybridization has shown that endothelial cells have increased levels of Factor VIII
antigen, the VEGF receptor, Kdr, endothelial nitric oxide synthase and endothelin-1. It is
possible that these endothelial markers can be applied to diagnose early lesions.
It is not known at what stage during the evolution of PPH that endothelial cell
proliferation occurs since it has not been consistently reported by all pathologists. Its
presence, if confirmed, would suggest that a somatic mutation, rather than non-selective
cell proliferation in response to injury, accounts for the growth advantage of endothelial
cells in PPH.
Smooth Muscle Cells
Heterogeneity exists in the smooth muscle cells and
fibroblast populations. Like the endothelium, the relationships between phenotype and
function need clarification. There needs to be emphasis on the synthesis of matrix
components and the modulation of phenotype to degrade and synthesize specific components.
Interconversion may occur between cell types (i.e., fibroblast to smooth muscle cell,
endothelium to smooth muscle cell), as well as the possibility of new vessel formation.
With respect to the adventitial fibroblast, it manifests a peculiar response to physical
stress in relation to matrix production. Finally, information from the study of normal
vascular development and differentiation needs to be applied to the pathology of pulmonary
In the large muscular and elastic arteries, smooth muscle cell hypertrophy and
increased connective tissue and extracellular matrix is found. Dissolution of the elastic
lamina is also a frequent finding. In the sub-endothelial or intimal layer, increased
thickness may be the result of both recruitment and/or proliferation of smooth muscle-like
cells. It is possible that precursor smooth muscle cells are in a continuous layer in the
sub-endothelial layer along the entire pulmonary artery. These cells are similar to the
pericytes that are responsible for the appearance of muscle in normally non-muscular
arteries and that contribute to the intimal thickening in larger arteries.
The complexity of the remodeling in the media and adventitia is in part due to the
presence of different smooth muscle cell types in several layers of the wall. Alterations
in phenotype of the different layers of smooth muscle cells may contribute to the
maintenance of PPH. The finding of a distinct smooth muscle cell type in the pulmonary
artery needs further exploration. The phenotypes of smooth muscle cells are likely to have
different functions and metabolic activity in each layer.
Alterations in the extracellular matrix secondary to
proteolytic enzymes appear to contribute to the pathology in an important way. Matrix
degrading enzymes can release mitogenically active growth factors that stimulate smooth
muscle cell proliferation. In addition, elastase and matrix metalloproteinases can
contribute to the up-regulation of the proliferation as well as the glycoprotein tenascin
through a b -3 integrin-mediated
transcriptional control mechanism. This could explain robust cellular proliferation in the
presence of excess deposition of a tenascin rich matrix. The degradation of elastin has
also been shown to stimulate up-regulation of the glycoprotein fibronectin which
stimulates smooth muscle cell migration.
The Plexiform Lesion
The plexiform lesion remains a mystery. It is possible
that it represents endothelial cells that are involved prominently in angiogenesis,
perhaps akin to a neoplastic process. Morphologically they represent a mass of
disorganized vessels with proliferating endothelial cells, smooth muscle cells,
myofibroblasts and macrophages and arise from preexisting, presumably parent pulmonary
arteries. Several studies have shown the involvement of growth factors that have been
implicated in angiogenesis. Whether the plexiform lesion represents impaired proliferation
or angiogenesis remains unclear.
CLASSIFICATION OF PULMONARY HYPERTENSION
It is recommend that the previous pathological
classification of pulmonary vascular disease be abandoned. It has been found to be too
restrictive and the classes and grades do not correlate with the clinical and hemodynamic
findings in a consistent prognostic fashion outside of congenital heart disease. Nor does
the graded classification system aid in clarifying the pathogenesis of the many causes of
pulmonary vascular disease.
Rather than classifying the pathological abnormalities, we recommend the use of a new
protocol designed to improve our understanding of the clinical picture, which is
descriptive rather than prescriptive. We also encourage the application and interpretation
of new histochemical and molecular biologic techniques. The pathologist is expected to
interpret pathological findings in the light of the clinical and hemodynamic information,
and to give guidance to the clinician by commenting on whether the findings are consistent
with, or help explain, the clinical findings in light of our present understanding. The
protocol should help ensure that the description of the findings be comprehensive,
reproducible and be easy to follow by all pathologists.
The following structures should be examined and noted:
Elastic, pre- and intra-acinar
arteries, microvessels, post-acinar and intra-acinar veins, capillaries, lymphatics, and
bronchial vessels. The vessel lumen should be commented on with respect to thrombi (recent
or old) and abnormal cellular and matrix components.
(a) Cellular components (endothelial cells and smooth muscle
(b) Matrix (elastin, collagen, mucopolysaccarides)
(a) Pattern (eccentric or concentric)
(b) Cellular components (smooth muscle and/or other cells)
(a) Cellular components (fibroblasts)
Vascular Lesions: Dilatation complexes, plexiform lesions, fibrinoid necrosis, arteritis,
(a) Types (neutrophil cells and mononuclear cells)
(b) Sites (perivascular or vascular wall)
Identify arteries by type of accompanying airways. An assessment of the number of
affected vessels in proportion to total vessels at a given airway level should be given.
The number of vessels in relation to the alveoli should be determined.
II. Lung Tissue
Pre- and intra-acinar airway, alveoli, interstitium, and pleura
The description should include:
H and E, pentachrome, a-actin, factor VIII and
Description of state of inflation and adequacy of sample size, airway and parenchyma
including evidence of associated parenchymal disease
Any other abnormalities or hemorrhage
Interpretation of the pathologic findings should be made in relation to the
biochemical, radiologic, clinical and hemodynamic findings, to help guide the clinician.
Are the pathologic findings consistent with the clinical picture? A diagnosis should be
made where possible.
Prof. Sheila G. Haworth, Chair University of London (London, UK)
Marlene Rabinovitch, MD, Chair The Hospital for Sick Children (Toronto, Canada)
Barbara Meyrick, PhD Vanderbilt University (Nashville, USA)
Rene Michel, MD McGill University (Montreal, Canada)
Giuseppe G. Pietra, MD University of Pennsylvania (Philadelphia, USA)
Julia M. Polak, MD Imperial College School of Medicine (London, UK)
Lynne M. Reid, MD Harvard Medical School (Boston, USA)
Rubin Tuder, MD University of Colorado Health Sciences Center (Denver, USA)
The aim of research in pathobiology is to discover the
molecular process(es) behind the complex vascular changes associated with pulmonary
Progress already realized from research in pathobiological mechanisms include:
- A description of phenotypic changes in endothelial and smooth muscle cells in
hypertensive pulmonary arteries
- Recognition that cell proliferation contributes to the structural changes associated
with the initiation and progression of pulmonary hypertension
- Recognition that apoptosis contributes to hypertensive pulmonary vascular disease
- Recognition of the role of matrix proteins and matrix turnover in vascular remodeling
- Recognition of the importance of hemodynamic influences on the disease process
- The development of a rationale for effective treatments directed towards specific
It is clear that gene expression in pulmonary vascular cells responds to environmental
factors, growth factors, receptors, signaling pathways and genetic influences, which
interact with each other. Examples of effector systems controlled by gene expression
- Transmembrane transporters
- Ion channels
- Transcription factors
- Modulators of apoptosis
- Cell to cell interactive factors (e.g., integrins and membrane receptors)
- Extracellular matrix turnover
- Growth factors/cytokines and chemokine networks
The levels of investigation in the pathobiology of
pulmonary hypertension include biochemical, cellular, integrated system and experimental
models, and measurements in humans. Potentially important pathophysiologic processes which
have been identified from descriptive studies from patients are listed below. In most
cases, it remains unclear whether the observations made are a cause or consequence of the
Inhibition of the voltage regulated (Kv) potassium
channel by hypoxia or drugs can produce vasoconstriction and has been described in
pulmonary artery smooth muscle cells harvested from patients with PPH. It is therefore
possible that defects in the potassium channel of pulmonary resistance smooth muscle cells
are involved in the initiation and/or progression of pulmonary hypertension. It is
possible that a genetic defect related to potassium channels in the lung vessels of PPH
patients leading to vasoconstriction is central to the development of PPH is some
An imbalance may exist in the vasoconstricting and
vasodilating mediators or substances involved in control of pulmonary vascular tone. These
include the prostacyclin versus thromboxane ratio, an increase in endothelin, a decrease
in nitric oxide production or release of other vasoactive substances yet to be described.
In addition, other factors might be involved such as serotonin, platelet derived growth
factor, angiotensin, or the loss of pulmonary vascular prostacyclin synthase gene
expression. Vasoconstrictors may also serve as factors or co-factors which stimulate
smooth muscle growth or matrix elaboration.
Prostacyclin Synthase Expression
The loss of the expression of the prostacyclin
synthase enzyme and gene in lungs of patients with severe pulmonary hypertension is
consistent with a decrease in pulmonary prostacyclin production. The loss of prostacyclin
synthase expression is likely one manifestation of an altered pulmonary hypertensive
endothelial cell phenotype.
Nitric Oxide Production and Chemistry
Reduced expression of nitric oxide synthase in the
endothelium of patients with pulmonary hypertension has been demonstrated and correlates
inversely with the extent and severity of morphologic lesions. Although it is unsettled as
to whether or not this a cause or result of the disease, it is consistent with endothelial
dysfunction underlying PPH as part of the disease process. Nitric oxide is important in
the signal transduction of angiogenesis, as VEGF receptor activation results in increased
nitric oxide production. Similarly, the expression of endothelin 1 is inversely related to
that of nitric oxide synthase. These findings suggest that whether or not abnormal
endothelial function is the underlying cause of PPH, the progression of the disease is
invariably accompanied by a worsening of endothelial function that itself can promote
Mediators of inflammation can cause vasoconstriction
and cell growth in animal models where inflammation is associated with pulmonary
hypertension. The presence of mast cells in the pulmonary vasculature of patients with
PPH, and increased levels of TGF-ß, interleukin 1 and 6, and the chemokine MIP 1a has been described in patients with
PPH. 5-lipoxygenase (5-LO), and 5-lipoxygenase activating protein (FLAP) over-expression
have also been described in PPH.
Serotonin is a pulmonary vasoconstrictor and growth
factor for vascular smooth muscle cells. It has not been established whether serotonin is
essential to PPH, but elevations of plasma serotonin levels and impaired platelet storage
of serotonin in patients with PPH have been described, and these have persisted in
patients with PPH following lung transplantation.
Misguided angiogenesis has been suggested as one
mechanism for the development of plexiform lesions. One study has suggested that
monoclonal expansion of endothelial cells occurs in PPH and is the basis for the plexiform
lesion, whereas plexiform lesions in secondary pulmonary hypertension are polyclonal,
suggesting that they occur via pathogenetically different routes. It is possible that
medial hypertrophy and hyperplasia are early changes that result from misguided
angiogenesis, as a consequence of a phenotypically altered endothelial cell.
Thrombosis in situ of the pulmonary vascular bed has
been proposed as a causative or contributing feature of pulmonary hypertension.
Abnormalities in platelet activation and function, and biochemical features of a
procoagulant environment within the pulmonary vasculature support a potential role of
thrombosis in disease initiation in some patients. The interaction between growth factors,
platelets, and the vessel wall suggest that thrombosis may play a fundamental role between
many of the described pathobiologic processes in PPH and disease progression.
Hemodynamics and Shear Stress
Several studies suggest that local hemodynamics can
influence pulmonary vascular remodeling. A classic example is the pulmonary hypertension
that occurs in congenital systemic to pulmonary shunts. It is believed that endothelial
cells release mediators that induce vascular smooth muscle cell growth. Experimental data
suggests that medial hypertrophy can be converted into a neointimal pattern when pulmonary
vascular injury is coupled with increased blood flow. These neointimal lesions are
composed of smooth muscle cells since they are immunoreactive to anti-a smooth muscle actin antibody. It is
now accepted that hemodynamic shear stress acts through the endothelium to regulate vessel
tone and in the chronic restructuring of blood vessels. Thus, the endothelium serves as a
complex mechanical signal transduction interface between blood flow and the vessel wall.
Several studies demonstrate persistent matrix protein
synthesis in pulmonary arteries obtained from patients with severe PPH. The observation
that these pulmonary arteries are actively remodeling provides the rationale for
developing pharmacologic inhibitors of remodeling that may halt, or even reverse,
progression of disease.
FUTURE GOALS OF PATHOBIOLOGIC
To discover the final common pathways for pulmonary hypertensive diseases
To identify candidate genes for sporadic and familial PPH
To identify the causative molecular process that are linked to epidemiologic risk
To develop molecular biochemical and physiologic tests to monitor and diagnose the
To develop new treatments based on established pathobiologic mechanisms
Prof. Timothy Higenbottam, Chair The University of Sheffield Medical School
Prof. Robert Naeije, Chair Erasme Hospital (Brussels, Belgium)
Norbert F. Voelkel, MD, Chair University of Colorado Health Sciences Center (Denver,
Mitchell D. Botney, MD Washington University-St. Louis, USA)
Brian Christman, MD Vanderbilt University (Nashville, USA)
Adel Giaid, MD McGill University (Montreal, Canada)
Charles A. Hales, MD Harvard Medical School (Boston, USA)
Philippe Herve, MD Marie Lannelongue Centre Chirurgica (LePlessis Robinson, France)
Joseph Loscalzo, MD, PhD Boston University (Boston, USA)
E. Kenneth Weir, MD University of Minnesota (Minneapolis, USA)
Risk Factors and
for Pulmonary Hypertension
A risk factor for pulmonary hypertension is any factor
or condition that is suspected to play a causal or facilitating role in the development of
the disease. Because risk factors relate to the probability of occurrence of the disease,
they must be present prior to the onset of the disease. Risk factors may include drugs,
chemical products, diseases or a clinical state (age, gender). When it is not possible to
determine whether a factor was present before the onset of the PPH, and thus it is unclear
whether it played a causal role, the term "associated condition" is used.
Associated conditions can be diseases that occur together with primary pulmonary
hypertension, and thus are the result of a common risk factor. When associated conditions
appear after the onset of PPH, it may be possible that PPH is a risk factor for that
Conclusions regarding the causal relationship between risk factors and the development
of PPH relate to the magnitude of the association, the temporality of the association, and
consistency of the observations. The clinical features of PPH in patients with known risk
factors are generally determined by the severity of the PPH, and whatever influences the
risk factor has on the overall medical condition. For example, the association of PPH and
cirrhosis would have the combined clinical features of PPH and liver disease.
The exact mechanism by which the risk factors produce PPH has not been established.
Given the fact that the absolute risk is generally low, factors of individual
susceptibility are likely to play an important role.
The following risk factors have been categorized based on the strength of the
association with PPH and their probable causal role. "Definite" indicates an
association based on several concordant observations, including a major controlled study
or a clear epidemic. Definite risk factors are considered to play a causal role in the
development of the disease. "Very likely" indicates several concordant
observations (including large case series and studies) that are not attributable to
considered biases, or a general consensus among experts. "Possible" indicates as
association based on case series, registries, or expert opinions. "Unlikely"
indicates risk factors that have been proposed but have not been found to have any
association from controlled studies.
A. Drugs and Toxins
- Toxic Rapeseed Oil
2. Very Likely
- Chemotherapeutic Agents
- Oral Contraceptives
- Estrogen Therapy
- Cigarette Smoking
B. Demographic and Medical Conditions
- Systemic Hypertension
2. Very likely
- Portal Hypertension / Liver Disease
- Collagen Vascular Diseases
- Congenital Systemic-Pulmonary Cardiac Shunts
RISK FACTORS AND ASSOCIATED CONDITIONS SUBCOMMITTEE
Lucien Abenhaim, MD, Chair McGill University
Prof. Gerald Simonneau, Chair
Hospital Antoine-Beclere (Clamart, France)
Miguel A. Gomez-Sanchez, MD
Hospital Universitario Doce de Octubre (Madrid, Spain)
Didier Lebrec, MD Hospital Beaujon
Rudolf Speich, MD University
Hospitals (Zurich, Switzerland)
PPH has been diagnosed in families worldwide.
Currently there are 72 known families in the U.S., 10 in Australia, 8 in England, 3 in
Canada and 1 in Germany. The prevalence of genetic or familial PPH is uncertain but is at
least 6% of all PPH cases and may be considerably higher.
The transmission and development of PPH in families has many unique features. The age
of onset is variable and the penetrance is incomplete. Many individuals in families with
PPH inherit the gene and have progeny with PPH yet never develop PPH. The observation that
there are fewer males born in PPH families than in the population at large suggests that
the PPH gene might influence fertilization or cause male fetal wastage.
Patients with familial PPH have a similar female to male gender ratio, age of onset and
natural history of the disease as those with "sporadic" PPH. The documentation
of familial PPH can be difficult since remote common ancestry occurs in patients with
apparently sporadic PPH, and skipped generations due either to incomplete penetrance or
variable expression can mimic sporadic disease. Because the clinical and pathologic
features of familial and sporadic PPH are virtually identical, it seems likely that the
same gene(s) may be involved in both forms of the disease. It also seems likely that the
disease will not be due to an abnormal gene product resulting from a mutation, but will be
due to abnormal production or regulation of a normal gene product.
Vertical transmission has been demonstrated in as many as five generations in one
family and is highly indicative of a single dominant gene which is believed to be
autosomal for PPH. Genetic anticipation has been evident in familial PPH since early
reports. Trinucleotide repeat expansion, originally described in several neurologic
disorders, remains the only known biologic explanation for genetic anticipation in PPH and
raises the possibility that the pathogenesis of familial PPH might have a neurologic
basis. The entire spectrum of pathologic features associated with sporadic PPH, including
plexogenic arteriopathy, thromboembolic arteriopathy, veno-occlusive disease and pulmonary
capillary hemangiomatosis have been reported in different families with PPH.
The locus of a gene linked to familial PPH has been identified on chromosome 2q31-32,
and analysis of the genome containing the gene has been reduced to less than 7 million
base pairs. Investigators have reported positive results of microsatellite marker
investigations which link familial PPH to the same 25-27 region on chromosome 2q31-32. PPH
1 is the Human Genome Organization approved designation DGB:1381541. The clinical
transmission of the gene is typical of other genetic diseases that are based on expanded
trinucleotide repeats, but may involve abnormal promoter or modifier gene functions as
well. The low penetrance of this gene confers only about a 10-20% likelihood of developing
Counseling Patients with Familial PPH
A complete family history should be obtained on every
patient with PPH in order to explore the possibility of familial disease. Because lifetime
penetrance is only 10-20% even if the gene is present, the likelihood of a first degree
relative being affected when only one person in a family has PPH is estimated at .6-1.2%.
If there is a second case known in the family, the risk rises to 5-10% lifetime. Based on
current data, it is unlikely that screening the family members for the presence of disease
will be of value when one member of the family has PPH. Children of an affected parent,
with familial PPH, have only a 5-10% lifetime risk of developing the disease. Although
clinical screening of asymptomatic family members will have a low yield, individual
clinicians and families may opt to do so because of the severity of the disease.
Most experts currently advise against recommending genetic testing of family members in
families with familial PPH because knowledge of the gene and its relationship to the
disease is not advanced enough to provide true informed consent to anyone requesting the
test. However, in large families where a sufficient number of DNA samples can be
collected, it is possible to provide information on carrier status by constructing genetic
Although PPH has been associated with autoimmune
phenomena, the association remains unclear. The data suggest that a subset of patients
with PPH may have a genetically programmed and immunologically mediated component to their
pulmonary hypertension which may predispose them to developing a diagnosable connective
tissue disease over time.
At the present time efforts are being focused towards
the actual identity of the PPH 1 gene. This will allow studies of gene regulation and
function, the use of transgenic and knockout animal models, as well as transfection with
native missense plasmids to clarify the pulmonary vascular and embryological and systemic
effects of the gene and its product. It is conceivable that the gene may be highly
polymorphic. If it contains an unstable trinucleotide repeat expansion, then the number of
repeats will likely determine the penetrance and probably the severity of the disease.
GENETICS OF PULMONARY HYPERTENSION SUBCOMMITTEE
David Langleben, MD, Chair McGill University (Montreal, Canada)
John H. Newman, MD, Chair Vanderbilt University (Nashville, USA)
C. Gregory Elliott, MD University of Utah (Salt Lake City, USA)
James E. Loyd, MD Vanderbilt University (Nashville, USA)
Jane H. Morse, MD Columbia University (New York, USA)
John Phillips, MD Vanderbilt University (Nashville, USA)
Richard C. Trembath, MD University of Leicester (Leicester, UK)
Diagnosis and Assessment of Pulmonary Hypertension
The diagnostic strategy for evaluating patients with pulmonary hypertension is well
accepted with a high degree of consensus among experienced clinicians. Utilizing current
medical technology, the correct diagnosis and assessment of the severity of pulmonary
hypertension in a given individual can be made with a high level of confidence. The
consensus regarding the general diagnostic approach to pulmonary hypertension now permits
focusing on specific problematic areas.
SCREENING FOR PULMONARY
Screening appropriate patient populations may lead to
the early identification of pulmonary hypertension in asymptomatic or minimally
symptomatic individuals, or in symptomatic patients in whom the diagnosis was not
previously suspected. This could allow early initiation of treatments at a time when
dynamic or reversible pathogenic mechanisms are present, increasing the likelihood of a
successful treatment outcome. Screening tests should be noninvasive and low risk, if
possible, and have a relatively high sensitivity and specificity for detecting pulmonary
Screening may be appropriate in groups of patients at increased risk of developing
pulmonary hypertension. In such instances, general screening should always begin with a
thorough clinical interview to elicit symptoms consistent with pulmonary hypertension, and
a thorough physical examination to elicit physical findings consistent with the diagnosis.
When the history and physical examination are inconclusive, further diagnostic testing may
The following recommendations are made regarding specific subgroups of patients. A
transthoracic echocardiogram is currently the preferred screening test for the presence of
Connective Tissue Diseases
The Scleroderma Spectrum of Diseases
Because of the high prevalence of pulmonary hypertension in these patients, as well
as the availability of effective treatments, a transthoracic echocardiogram is recommended
to be performed annually in patients with or without symptoms of pulmonary hypertension.
Systemic Lupus, Rheumatoid Arthritis, and Other Connective Tissue Diseases
Because of the low prevalence of pulmonary hypertension, and the lack of
established effective treatment, a transthoracic echocardiogram is recommended only if
patients have symptoms suggestive of pulmonary hypertension.
Families of Documented PPH
A detailed family history should be taken at the time
the diagnosis of PPH is made in the proband. It is reasonable to consider a transthoracic
echocardiogram in the first degree relatives at the time of diagnosis, at any time
symptoms consistent with pulmonary hypertension arise, or every three to five years in
asymptomatic individuals. In addition, relatives should be made aware of symptoms
consistent with pulmonary hypertension. The basis for these recommendations is the greater
prevalence of familial PPH than previously reported, and the availability of effective
treatments. In addition, screening asymptomatic family members will help gather additional
information about the prevalence of familial PPH and the effectiveness of early
Liver Disease/Portal Hypertension
Because pulmonary hypertension in these patients
renders them at very high risk for liver transplantation, and because there is effective
treatment available, a transthoracic echocardiogram should be performed in all patients
when they are evaluated for liver transplantation.
Because of the low prevalence of pulmonary
hypertension in this subgroup, a transthoracic echocardiogram is recommended only in
subjects who are HIV positive if they have symptoms consistent with pulmonary
Patients with a History of Intravenous Drug
Because the prevalence of pulmonary hypertension is
uncertain in this subgroup, a transthoracic echocardiogram is recommended only in those
patients who have symptoms consistent with pulmonary hypertension.
Patients with a History of
Appetite-Suppressant Drug Use
Because of the low prevalence of pulmonary
hypertension in this subgroup, a transthoracic echocardiogram is recommended only in
patients who have symptoms consistent with pulmonary hypertension.
EVALUATION OF MILD PULMONARY HYPERTENSION
The widespread use of Doppler echocardiography in the
assessment of nonspecific cardiovascular symptoms or signs has led to occasional
observations of mildly increased right ventricular systolic pressure. Mild pulmonary
hypertension is defined as a systolic pulmonary artery pressure of 40-50 mmHg, which
corresponds to a tricuspid regurgitant velocity on Doppler echocardiography of 3.0-3.5
m/sec. The following recommendations are made regarding the assessment of mild pulmonary
Asymptomatic Individuals (Incidental
It is recommended that a Doppler echocardiogram be
repeated in six months along with a detailed history and physical examination.
It is recommended that signs of pulmonary hypertension
warrant right heart catheterization for confirmation of the hemodynamic findings. If the
right heart catheterization does not reveal pulmonary hypertension at rest, it is
recommended that pulmonary hemodynamics be measured during exercise. Patients in whom mild
pulmonary hypertension exists at rest, or develops with exercise, should be managed like
other patients with pulmonary hypertension.
High Risk Individuals
Individuals who are asymptomatic but at high risk of
developing pulmonary hypertension should have a Doppler echocardiographic exam repeated in
six months. If the presence of mild pulmonary hypertension is confirmed, they should
undergo the same evaluation as do patients with symptomatic pulmonary hypertension.
TESTING TO CHARACTERIZE PULMONARY HYPERTENSION
Recent advances in medical technology have greatly
improved noninvasive measurements rendering them more precise, reproducible, and
reflective of the underlying pathophysiology of the disease.
Echocardiography with Doppler
The following parameters are suggested for
- tricuspid regurgitant velocity
- pulmonary artery systolic flow acceleration time
- right ventricular ejection time
- right ventricular dimensions
- right ventricular volumetric data
- right ventricular index of myocardial performance
- timing of mid-systolic deceleration of right ventricular ejection
Echocardiography with Doppler may be useful in the follow-up of patients with pulmonary
hypertension to monitor progression of the disease and/or the response to therapy.
Magnetic Resonance Imaging (MRI)
The following parameters may be useful in evaluating
- right ventricular morphology
- right atrial morphology
- pulmonary artery morphology
- right ventricular function
The value of serial MRI scans in following the course of patients is not established.
Computed Tomography (CT) of the Chest
The following parameters may be useful in evaluating
- right ventricular morphology
- right atrial morphology
- pulmonary artery morphology
- right ventricular function.
It is recommended that a high-resolution chest CT scan also be performed to evaluate
the lung parenchyma and to detect the presence of pulmonary venocclusive disease.
The value of serial chest CT scans in following the course of patients is not
A six-minute walk test or a cardiopulmonary exercise
test is recommended in patients at the time of diagnosis and follow-up. Exercise tests
best characterize the functional impairment of patients with PPH, and their response to
Right Heart Catheterization
Right heart catheterization is recommended for all
patients who are undergoing an evaluation of pulmonary hypertension. Measurements during
catheterization should include the following:
- right atrial pressure
- right ventricular systolic and end-diastolic pressure
- pulmonary artery systolic, diastolic, and mean pressure
- pulmonary capillary wedge pressure
- systemic and pulmonary arterial oxygen saturation
- cardiac output
It is recommended that all patients undergo acute testing with a short-acting
vasodilator to determine vasodilator responsiveness at the time of their initial right
heart catheterization. The following vasodilators are recommended:
- intravenous epoprostenol sodium
- inhaled nitric oxide
- intravenous adenosine
Patients who appear responsive to acute vasodilator testing may have a favorable
response to treatment with oral calcium channel blockers. Although there is no consensus
about the definition of vasodilator responsiveness, a minimum acceptable response would be
a reduction in mean pulmonary artery pressure of 10 mm/Hg associated with either no change
or an increase in cardiac output. Patients who do not manifest responsiveness to acute
vasodilator challenge are unlikely to have clinical benefit from oral calcium channel
Assessment of Pulmonary Arterial Impedence
Measurements of the impedence of the pulmonary vascular bed, using the acceleration
time interval measurements (AcT), may provide additional information about right
ventricular performance. Impedence parameters may better reflect true right ventricular
afterload and provide hemodynamic information beyond that derived from measurements of
pressure and flow. Accurate assessment of impedence can be done at the time of cardiac
catheterization using high-fidelity multisensor pressure and velocity transducers.
Although pathologic assessment of the lung may provide
insights into histopathologic characteristics of pulmonary hypertensive states, the
procedure entails a risk and there is little evidence that it provides additional
clinically useful information over careful noninvasive and hemodynamic assessment in most
patients. Lung biopsy cannot be recommended as a part of the routine evaluation of
patients with suspected PPH. It should be considered when there appears to be a specific
indication, such as a diagnosis of active vasculitis.
DIAGNOSIS AND ASSESSMENT SUBCOMMITTEE
Alfred P. Fishman, MD, Chair University of Pennsylvania (Philadelphia, USA)
Michael D. McGoon, MD, Chair Mayo Clinic (Rochester, MN USA)
Irina E. Chazova, MD Ministry of Health of the Russian Federation (Moscow, Russia)
Peter F. Fedullo, MD University of California (San Diego, USA)
Prof. Meinhard Kneussl University of Vienna (Vienna, Austria)
Andrew J. Peacock, MD Western Infirmary (Glasgow, Scotland)
Adam Torbicki, MD National Institute of Tuberculosis and Lung Disease (Warsaw, Poland)
Medical Therapy of
Over the past 25 years there has been considerable
experience with a variety of medications for the treatment of primary pulmonary
hypertension. The clinical experience with these medications are summarized.
CALCIUM CHANNEL BLOCKERS
Calcium channel blockers are a chemically
heterogeneous group of compounds that inhibit calcium influx through the slow channel into
cardiac and smooth muscle cells. Their usefulness in PPH is believed to be based on the
ability to cause vasodilatation of pulmonary vascular smooth muscle. They also produce
electrophysiologic effects, possess negative inotropic properties and cause reflex
increases in beta adrenergic tone.
The data demonstrates that a minority (approximately
20%) of patients with PPH will respond to oral calcium channel blockers, documented by an
improvement in symptoms and exercise tolerance, hemodynamics via a reduction in pulmonary
artery pressure and an increase in cardiac output, and survival. Although most studies
have used calcium channel blockers at relatively high doses, the optimal dosing of
patients with PPH is uncertain. The direct effect of calcium channel blockers on pulmonary
vessel wall biology is unknown.
Patients with no evidence of an acute hemodynamic response to these drugs are unlikely
to benefit from chronic therapy. Because of the frequent reporting of significant adverse
effects of calcium blocker in these patients, which include systemic hypotension,
pulmonary edema, right ventricular failure, and death, it is not recommended that calcium
channel blockers be used in patients in whom acute effectiveness has not been
Enhanced effects of calcium channel blockers when used
in conjunction with intravenous vasodilators and oral thromboxane synthase inhibitors has
been reported. It is recommended that the use of calcium channel blockers in combination
with other treatments be pursued.
As the cause of death in patients with PPH is
primarily right heart failure, the use of drugs that will improve right ventricular
performance is warranted. Currently there are no data on the use of chronic inotropic
therapy as a treatment of PPH. The experience of an increased mortality in patients with
left heart failure treated with a chronic inotropic therapy is of concern.
Class I Agents
These agents augment contractility by increasing intracellular cAMP and calcium.
The short term use of parenteral inotropes may be of benefit in some circumstances.
Class II Agents
Digoxin has been shown to increase cardiac output and reduce circulating
norepinephrine acutely in patients with PPH. Digoxin has also been shown to be chronically
effective in patients with left ventricular failure. Digoxin is used by some experts in
the management of PPH for these reasons.
A better understanding of the neurohumoral and
hemodynamic effects of inotropic therapy in patients with PPH is necessary. Strategies
should also be developed to attempt to restore normal gene expression of sarcomere
proteins to improve the contractile performance of the cardiac myocytes.
Histologic data demonstrating thrombotic lesions in
small pulmonary arteries in a large percent of patients with PPH and biochemical data
consistent with a hypercoaguable state in some patients with PPH provide a rationale for
the use of anticoagulants in PPH.
Clinical data supporting the chronic use of
anticoagulation is limited but supportive. Warfarin has been shown to be associated with
improved survival in one retrospective study of PPH, one retrospective study of patients
with PPH associated with the use of aminorex, and one prospective study of PPH. The
optimal dose of warfarin in these studies was not determined. The range of anticoagulation
that is recommended is an INR of 1.5 to 2; however, different clinical circumstances may
require adjustment of the range.
New antithrombotic and anticoagulant drugs are being
evaluated for several different clinical entities. Drugs that might be of promise in
patients with PPH include monoclonal antibodies and other agents that block the
glycoprotein IIb/IIIa platelet receptor, thromboxane synthase inhibitors and receptor
blockers, and heparins and heparin-like compounds.
The use of prostacyclin or an analogue as a treatment
of PPH is supported by the demonstration of an imbalance of thromboxane to prostacyclin
metabolites in patients with PPH, and the demonstration of a reduction in prostacyclin
synthase in the pulmonary arteries of patients with PPH.
Continuous intravenous prostacyclin has been evaluated
in prospective, randomized clinical trials of PPH. The results confirm an improvement in
exercise tolerance, hemodynamics, and survival in patients who are Functional Class III
and Class IV. The mechanism of action of the chronic effects of prostacyclin is unknown in
these patients, but it is likely multifactorial. Clinical data suggests that it lowers the
pulmonary artery pressure, raises the cardiac output, improves systemic oxygen transport,
and possibly reverses pulmonary vascular remodeling. Studies have also demonstrated that
the lack of an acute response to prostacyclin does not preclude a chronic beneficial
response. The development of tolerance to the effects of intravenous prostacyclin is
common, and appears to respond to periodic dose escalation. However, the optimal dosing of
intravenous prostacyclin for PPH remains uncertain.
Studies are necessary to clarify the mechanisms of
action of prostacyclin on cardiac and vascular tissue. A better understanding of how to
determine the optimum dosing of patients on intravenous prostacyclin is essential.
Alternate delivery systems may enhance efficacy, improve safety, and reduce side effects.
Trials looking at the effectiveness of prostacyclin analogues administered subcutaneously,
by inhalation, and orally, are warranted. The use of these agents in less severely ill
patients will be desirable as less complex delivery systems become available. Drugs that
increase endogenous prostacyclin production should be pursued.
Nitric oxide activates guanylate cyclase in pulmonary
vascular smooth muscle cells which increases cGMP and decreases intracellular calcium
concentration, thereby leading to smooth muscle relaxation. When inhaled, the rapid
combination of nitric oxide with hemoglobin inactivates any nitric oxide diffusing into
the blood, preventing systemic vasodilatation. Consequently nitric oxide is a potent and
selective pulmonary vasodilator when administered by inhalation.
Although there is a considerable experience in the use
of nitric oxide as a short-term treatment of pulmonary hypertension in a variety of
clinical situations, the role of nitric oxide as a chronic therapy for PPH remains
investigational. The mechanism of beneficial effects of nitric oxide in PPH, both acutely
and chronically are likely multifactorial.
More data is needed regarding the long-term efficacy
and safety of chronic nitric oxide as inhalation therapy. Preliminary studies suggest the
pursuit of nitric oxide potentiating compounds, such as phosphodiesterase inhibitors, is
warranted. Histologic studies demonstrating reduced levels of nitric oxide synthase in the
pulmonary vasculature of patients with PPH provides justification for the development of
gene replacement therapy for this disease.
FUTURE DIRECTIONS FOR MEDICAL
Considerable promise exists in the development of
medical therapy for PPH following a wide variety of approaches. These include:
- studies of myocardial protein and genotypes
- development of vascular antiproliferative agents (including angiotensin converting
enzyme inhibitors and endothelin receptor blockers)
- development of agents that affect ion channel function (such as potassium channel
- studies of endothelial derived substance synthesis and metabolism
- studies of genotype and gene expression
- studies evaluating multimodal/combination therapies
Studies of the pathobiology of PPH have demonstrated abnormalities in cellular function
of different cell types and sequential changes in vascular morphology and function leading
to remodeling. These observations provide targets for the use of several agents in
combination, and/or the staging of therapies. In addition to the reversal of remodeling,
stimulation or enhancement of normal endothelial cell function may be possible.
MEDICAL THERAPY SUBCOMMITTEE
Robyn J. Barst, MD, Chair Columbia University (New York, USA)
Bruce H. Brundage, MD, Chair UCLA School of Medicine (Los Angeles, USA)
Stuart Rich, MD, Chair Rush Medical College (Chicago, USA)
Lewis J. Rubin, MD, Chair University of Maryland (Baltimore, USA)
Nazzareno Galie, MD Universita degli Studi di Bologna (Bologna, Italy)
Stefan Janssens, MD, PhD University of Leuven (Leuven, Belgium)
Jiri Widimsky, MD Charles University (Prague, Czech Republic)
Warren Zapol, MD Harvard Medical School (Boston, USA)
for Pulmonary Hypertension
The rationale for the creation of an atrial septostomy
in PPH is based on experimental and clinical observations suggesting that an intra-atrial
defect allowing right to left shunting in the setting of severe pulmonary hypertension
might be of benefit. Although there exists a worldwide experience in over 60 patients, the
procedure should still be considered investigational. Nonetheless, atrial septostomy may
represent a real alternative for selected patients with severe PPH. Indications for the
- recurrent syncope and/or right ventricular failure despite maximum medical therapy
- as a bridge to transplantation if deterioration occurs despite maximum medical therapy
- when no other option exists
As the disease process in PPH appears to be unaffected by the procedure, the long-term
effects of an atrial septostomy must be considered to be palliative.
The procedure-related mortality with atrial septostomy
in patients with PPH is high, and thus the following recommendations are made to minimize
- atrial septostomy should only be attempted in institutions with an established track
record in the treatment of advanced pulmonary hypertension and an experience in performing
atrial septostomy with low morbidity
- atrial septostomy should not be performed in the patient with impending death and severe
right ventricular failure, on maximal cardiorespiratory support.
Predictors of procedure-related failure or death include:
- a mean right atrial pressure > 20 mmHg
- a PVR index > 55 U·M2
- a predicted one year survival less than 40%
Candidates for atrial septostomy should have a systemic arterial oxygen saturation on
room air of greater than 90%. During the atrial septostomy procedure it is recommended
that the patient have the following:
- mild and appropriate sedation to prevent anxiety
- supplemental oxygen
- careful monitoring of hemodynamics with particular monitoring of the systemic arterial
The endpoint for the procedure should be considered a reduction in systemic arterial
oxygen saturation of 5-10%. It is also recommended that the procedure be performed in a
stepwise manner, to create the smallest possible septal defect that will produce
Before and after septostomy, transfusion of packed red blood cells or the use of
erythropoietin may be necessary to increase oxygen delivery. Chronic anticoagulation is
The optimal timing of the intervention remains uncertain. Investigations should address
whether or not the intervention should be performed earlier in the course of the disease.
The mechanisms responsible for beneficial effects of atrial septostomy remain unclear.
Possibilities that exist include:
Increased oxygen delivery at rest and/or with exercise
Reduced right ventricular end diastolic pressure or wall stress
Improvement of right ventricular dysfunction by Frank Starling mechanism or relief of
Long-term effectiveness and possible undesirable effects need to be studied.
ATRIAL SEPTOSTOMY SUBCOMMITTEE
Julio Sandoval, MD, Chair Instituto Nacional de Cardiologia (Mexico City, Mexico)
Robyn J. Barst, MD Columbia University (New York, USA)
Stuart Rich, MD Rush Medical College (Chicago, USA)
Abraham Rothman, MD University of California (San Diego, USA)
for Pulmonary Hypertension
Transplantation is an effective treatment for patients
with advanced pulmonary hypertension. Since 1981, close to 1000 patients have undergone
either a single lung, double lung or heart-lung transplant for pulmonary hypertension
worldwide. Ages of recipients range from 2 months to 61 years. The operative mortality
ranges between 16-29% and is affected by the primary diagnosis. PPH recipients of a single
lung transplant appear to have a higher operative mortality than those undergoing
transplantation for other conditions, whereas recipients of double lung or heart-lung
transplant appear to have comparable results. The one year survival is between 70-75%, the
three year survival between 55-60% and five year survival between 40-45%. The longest
survival to date in a heart-lung transplant recipient has been more than 14 years.
Transplantation should be reserved for patients with
pulmonary hypertension who have progressed in spite of optimal medical management.
Advances in the medical therapy of PPH has improved the prognosis for many patients. As
progress is made in the medical management of patients with PPH, the indications for
transplant may evolve.
Patients should be referred for evaluation for transplantation at the appropriate time.
The course of the disease and the waiting time must be taken into account. Timing the
referral for transplantation depends on the patient's prognosis with optimal medical
management, the anticipated waiting time before transplantation in the region, and the
expected survival after transplantation. Guidelines for timing the referral include:
- NYHA Functional Class III or IV in spite of medical therapy
- When treatment with prostacyclin is initiated, or is failing, or is causing intolerable
There are several transplantation options. Acceptable results have been achieved with
heart-lung transplantation, bilateral lung transplantation, and single lung
transplantation. While there are advantages and disadvantages to each operation, there is
currently no consensus regarding the best procedure. The availability of donor organs
often influences the choice of procedure. It is possible that data on long-term survival
in transplant recipients may demonstrate a survival advantage of one procedure over
While traditional measures such as survival and cardiopulmonary function have been
emphasized, quality of life is equally important. Several studies have documented a
significant improvement in both overall and health-related quality of life after
heart/lung and lung transplantation for pulmonary hypertension. Only pilot studies have
addressed the issue of cost effectiveness. When considering the cost effectiveness of
transplantation, one needs to account for the anticipated medical care of the advanced PPH
patient who often requires frequent hospitalization, and the expense of newer therapies,
such as intravenous prostacyclin therapy at the present time.
Living related donor transplantation is controversial.
Although related living donor lung transplantation has been successful, there is very
limited experience in children and no known experience in adults with pulmonary
hypertension. Extreme caution is advised when considering this approach at this time.
Stuart W. Jamieson, MB University of California (San Diego, USA)
Elbert P. Trulock, MD Washington University (St. Louis, USA)
Prof. Magdi Yacoub British Heart Foundation (Middlesex, UK)
of Pulmonary Hypertension
A diagnostic classification of the various forms of
pulmonary hypertension can be helpful in communicating about individual patients and in
standardizing diagnosis and treatment. Pulmonary hypertension can be classified in many
ways. Several previous classifications have proved to be problematic.
The following is proposed to allow the categorization by common clinical features. This
classification reflects recent advances in the understanding of pulmonary hypertensive
diseases, and recognizes the similarity between primary pulmonary hypertension and
pulmonary hypertension of certain known etiologies.
(In keeping with the new diagnostic classification, a new pathologic classification of
pulmonary hypertension is proposed. The new recommendations for the pathologic
characterization of pulmonary hypertensive states are included in the Pathology section.)
1. Pulmonary Arterial
1.1 Primary Pulmonary Hypertension
1.2 Related to:
(a) Collagen Vascular Disease
(b) Congenital Systemic to Pulmonary Shunts
(c) Portal Hypertension
(d) HIV Infection
(e) Drugs / Toxins
Persistent Pulmonary Hypertension of the Newborn
2. Pulmonary Venous Hypertension
2.1 Left-Sided Atrial or Ventricular Heart
2.2 Left-Sided Valvular Heart Disease
2.3 Extrinsic Compression of Central
(a) Fibrosing Mediastinitis
(b) Adenopathy / Tumors
2.4 Pulmonary Veno-Occlusive Disease
3. Pulmonary Hypertension Associated with Disorders of the
Respiratory System and/or Hypoxemia
3.1 Chronic Obstructive Pulmonary Disease
3.2 Interstitial Lung Disease
3.3 Sleep Disordered Breathing
3.4 Alveolar Hypoventilation Disorders
3.5 Chronic Exposure to High Altitude
3.6 Neonatal Lung Disease
3.7 Alveolar-Capillary Dysplasia
4. Pulmonary Hypertension due to Chronic Thrombotic and/or
4.1 Thromboembolic Obstruction of Proximal
4.2 Obstruction of Distal Pulmonary Arteries
(a) Pulmonary Embolism (Thrombus, Tumor, OVA and/or parasites,
(b) In-situ Thrombosis
(c) Sickle Cell Disease
5. Pulmonary Hypertension due to Disorders Directly
Affecting the Pulmonary Vasculature
5.2 Pulmonary Capillary Hemangiomatosis
Functional Assessment *
A. Class I Patients with pulmonary hypertension
but without resulting limitation of physical activity. Ordinary physical activity does not
cause undue dyspnea or fatigue, chest pain or near syncope.
B. Class II Patients with pulmonary hypertension resulting in slight limitation
of physical activity. They are comfortable at rest. Ordinary physical activity causes
undue dyspnea or fatigue, chest pain or near syncope.
C. Class III Patients with pulmonary hypertension resulting in marked limitation
of physical activity. They are comfortable at rest. Less than ordinary activity causes
undue dyspnea or fatigue, chest pain or near syncope.
D. Class IV Patients with pulmonary hypertension with inability to carry out any
physical activity without symptoms. These patients manifest signs of right heart failure.
Dyspnea and/or fatigue may even be present at rest. Discomfort is increased by any