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Lung Disease
Pulmonary Arterial Hypertension:
An Update
John Granton, MD, Assistant Professor of Medicine, University of Toronto; Pulmonary
Arterial Hypertension Programme, University Health Network,Toronto, ON.
Moiz Zafar, MD, Resident, Respiratory Medicine, McMaster University, Hamilton,
ON; Pulmonary Arterial Hypertension Programme, University Health Network,
Toronto, ON.
Introduction
On first glance, a review of pulmonary
arterial hypertension (PAH) in a journal
that focuses on the health of the elderly
may seem out of place. PAH is typically
envisioned as a progressively disabling
disease in young females. However, PAH
is not a disease restricted to the young.
Indeed, 20% of the patients followed in
our pulmonary hypertension clinic are
over the age of 65. Although information
regarding the natural course of PAH has
been described in a report of the National Registry for Primary Pulmonary
Hypertension, this information is not representative of the elderly population.1 In
particular, given the greater prevalence of
comorbid conditions in the elderly, one
must be particularly vigilant in searching
for an underlying secondary cause of
PAH. Owing to a paucity of information
in this population, most of our comments
derive from our own observations of
PAH in the elderly and from inferences
made from their younger counterparts.
Definition
PAH is defined as an elevation in pulmonary arterial pressure greater than
25mmHg at rest or 30mmHg with exercise.2 In most instances, however, the
diagnosis of PAH is first made echocardiographically (ECHO). It is important to
emphasize that the ECHO definition of
PAH is less reliable. Although the typical
upper limit of normal for right ventricular systolic pressure (RVSP) is 40mmHg,
one is commonly confronted with either
an asymptomatic or mildly symptomatic
patient with mild elevations in RVSP at
rest. In general, the diagnosis of pul-
monary hypertension should not rest
solely on ECHO estimates of pulmonary
arterial pressure; secondary ECHO features and additional confirmatory tests
are required vide infra.
PAH is typically classified as being
either primary or secondary. The diagnosis of primary pulmonary hypertension (PPH) can be made only in the
absence of an identifiable systemic disease process. Primary PAH is thought to
arise as a consequence of biological and
chemical mediators acting on the pulmonary vasculature in potentially genetically susceptible hosts. Secondary
pulmonary hypertension (SPH) may be
a consequence of a large number of cardiac and respiratory disorders or other
systemic diseases. A recent reclassification of pulmonary arterial hypertension
by the World Health Organization was
developed to emphasize the similarities
between idiopathic or primary PAH and
secondary PAH (Table 1).2 Advances in
the understanding of the mechanisms
underlying the vascular changes in PAH
have contributed to the development of
successful therapeutic strategies. It
appears that some of the medical therapies initially targeted for primary PAH
also benefit patients with secondary
PAH. In this regard, although there is
diversity in the etiology of PAH, the therapeutic literature supports some uniformity of process.
Epidemiology
An estimated incidence of PPH in the
general population is one to two persons
affected per one million population. It is
more prevalent in females than in males,
with a ratio of 1.7:1. In a small case series
of patients with PAH over age 65, this
female predilection was also seen.3 However, reliable estimates of the incidence
and prevalence of secondary PAH in the
geriatric population are difficult to attain.
Secondary PAH is likely under-diagnosed and may be obscured by the
underlying medical condition.
Pathogenesis
The mechanisms underlying the development and progression of PAH are
incompletely understood. A range of systemic and regional vascular defects has
been implicated in the development of
PAH (Table 2).4 However, it is often
unclear whether the defect represents a
cause or consequence of the disease. The
extent to which these factors are causal
remains an active area of investigation.
Genetic susceptibility is recognized
as an underlying factor and much knowledge has been gathered from genetic
studies in kindreds with familial PPH.
Recently, mutations in a gene on chromosome 2q encoding BMPR-2 (Bone
Morphogenic Protein Receptor Type-2),
a member of the TGF-b receptor superfamily, have been described in both familial and sporadic forms of PAH.5,6 At
present, the relevance of the defect in the
gene coding for BMPR-2 in the elderly
patient has not been determined, and the
precise functional consequences of this
altered gene still need to be fully elucidated. The defect is currently thought to
code for a dysfunctional protein that
leads to unregulated smooth muscle and
possibly endothelial cell growth.7 It is
likely that a multistep process is required
in genetically susceptible individuals
before the genetic defect manifests clinically. Some environmental injury (hypoxia, anorexigens) or coexisting disease
(scleroderma, lupus) may potentially
incite a process leading to PAH by causing an initial vascular injury that in turn
leads to dysfunctional growth and repair
www.geriatricsandaging.ca 29
Pulmonary Arterial Hypertension
and the characteristic structural and functional vascular changes
in a susceptible individual.
The histological appearances of primary and secondary
PAH are indistinguishable. Several vascular lesions involving
the arteries have been described. Although a single form of vascular lesion may predominate in an individual, it is more
common that a range of these histological lesions are observed
Table 1
Diagnostic Classification of Pulmonary
Hypertension 2
Pulmonary Arterial Hypertension (PAH)
Primary PAH
– sporadic
– familial
PAH related to:
– collagen vascular disease
– congenital systemic to pulmonary shunts
– portal hypertension
– HIV infection
– drugs/toxins (e.g., anorexogens)
Pulmonary Venous Hypertension
Left-sided atrial or ventricular disease
Left-sided valvular heart disease
Extrinsic compression of central pulmonary veins
– fibrosing mediastinitis
– adenopathy / tumour
Pulmonary veno-occlusive disease
Pulmonary Hypertension Associated with Disorders of
the Respiratory System or Hypoxemia
Chronic obstructive pulmonary disease
Interstitial lung disease
Sleep-disordered breathing
Alveolar hypoventilation syndromes
Chronic exposure to high altitude
Pulmonary Hypertension due to Chronic Embolism
Thrombosis
– proximal
– distal
Sickle cell disease
Tumour/ova/parasites/foreign material (e.g., talc)
Pulmonary Hypertension due to Disorders Directly
Affecting the Pulmonary Vasculature
Inflammatory
– schistosomiasis
– sarcoidosis
Pulmonary Capillary Hemangiomatosis
30 GERIATRICS & AGING • November 2002 • Vol 5, Num 9
in a single patient. It is unclear if the prevalence of these lesions
differs across age groups. It has been suggested that lesions
which do predominate portend a worse prognosis and are less
responsive to vasodilator therapy.8
Functional Consequences of Altered Vasculature
The pulmonary circulation is normally a low-pressure circuit
with high capacitance and remarkably low resistance. Normally, under exercise conditions large increases in cardiac output are accommodated with only slight increases in pulmonary
arterial pressure. This is achieved through mechanisms of vascular recruitment and vascular distention. In PAH, there is effectively a reduction in the total cross-sectional area of pulmonary
vasculature. The resultant increase in pulmonary vascular resistance leads to elevations in pulmonary arterial pressures initially under exercise conditions, but which later progress to
sustained elevation at rest. Sustained elevation in pulmonary
arterial resistance in turn leads to right ventricular dilatation
and systolic dysfunction. Eventually, the right ventricle becomes
unable to maintain cardiac output even at rest, and is manifested as right ventricular failure and worsening symptoms. It
is important to emphasize the significance of the right ventricle
and that PAH is a disease characterized by a low cardiac
output (Figure 1).
Clinical Presentation
Due to the nonspecific nature of symptoms that patients with
PAH describe, the length of time from the onset of symptoms
to diagnosis may be prolonged. Consequently, many patients
present with quite advanced disease. In a study by Rich et al.,
Table 2
Observed Defects Variably Implicated in
Development of Pulmonary Arterial
Hypertension
Genetic
Defect in BMPR-2
Deranged cellular growth
Endothelium
Altered angiogenesis
Loss of barrier function
Vasoconstriction
↑ Endothelin
↑ Prostacyclin
↑/↓ Nitric oxide synthase
Abnormal K+ channels
Smooth muscle cells
Hypertrophy
Matrix
Growth factors (FGF, VEGF)
Elastases
Coagulation
↑ Thrombosis
↓ Platelet activating factor inhibitor
Autoimmunity
Positive ANA
Pulmonary Arterial Hypertension
Pulmonary Circulation
Figure 1
Pulmonary
artery
Normal
– pressure in pulmonary
artery < 25mmHg at rest
– low resistance in the
capillaries
Media
Lumen
Normal pulmonary
arteriole
Right
ventricle
Thickened
pulmonary
artery
Pulmonary Arterial
Hypertension
– elevation in pulmonary
pressure >25mmHg at rest
– right ventricular dilatation
– thickened pulmonary artery
Lumen
reduced
Media
thickened
Dilated right
ventricle
Hypertension
www.geriatricsandaging.ca 31
Pulmonary Arterial Hypertension
the average time from onset of symptoms to diagnosis was two
years.1 This delay in diagnosis may be particularly problematic for the elderly in whom it may be more difficult to distinguish
progressive symptoms from co-existing medical conditions.
Patients with both primary and secondary forms commonly
present with symptoms and signs related to right ventricular
dysfunction and reduced cardiac output (Table 3). Patients may
also experience angina due to ischemia of the right ventricle in
the setting of increased cardiac workload, even in the absence
of significant coronary artery disease.
Diagnostic Assessment
A meticulous history and pertinent physical examination in
conjunction with a high index of suspicion is essential in diagnosing PAH. The chest radiograph may show enlargement of
the pulmonary arteries, and right-sided cardiac silhouette.
Pleural effusions are not usually seen in even severe forms of
PAH, and require further explanation. Although there are
characteristic electrocardiographic changes (tall R wave in V1,
and S1 - Q3 - T3) from PAH, these findings are insensitive.
Echocardiography is the most useful imaging modality for
both detecting PAH and evaluating the presence of underlying cardiac disease. However, as mentioned earlier, echocardiography can be misleading in patients with mild elevations
in RVSP. These patients often have normal pulmonary arterial pressures during right heart catheterization and do not
demonstrate an abnormal increase with exercise. In other
patients, however, pulmonary arterial pressures do rise
abnormally during exercise, suggesting a reduction in capacitance and compliance of the pulmonary vasculature—characteristics of PAH. When evaluating patients with suspected
PAH, it is important to evaluate the right ventricle. Enlargement of the right atrium and ventricle, right ventricular
hypokinesis, septal flattening and tricuspid insufficiency are
characteristic of elevated right ventricular afterload. In addition, pericardial effusions (mild to moderate) are common.
Absence of right ventricular dilation or dysfunction reduces
the probability that the recorded RVSP is hemodynamically
significant. It is also important to evaluate left ventricular systolic and diastolic function. Left atrial dilation raises the possibility that the observed increase in RVSP is due to primary
left-sided cardiac abnormalities.
Once the diagnosis of PAH is established, a thorough
evaluation is required to exclude secondary causes. Secondary causes generally can be determined through a
detailed history or clinical examination. In general, the
approach to evaluating the causes of PAH follows from the
various etiologies described in Table 1 and are listed in Table
4. It is important to emphasize that PAH singularly cannot
account for significant arterial hypoxemia. In these patients,
Table 4
Laboratory Evaluation of Patients with
Pulmonary Arterial Hypertension
Electrocardiogram
Chest X-ray
Surface and trans-esophageal echocardiography
CT scan of the thorax (angiographic and/or high resolution
protocols)
Pulmonary function tests
V/Q scan (if CT angiogram is not done)
Assessment of exercise capacity—six minute walk distance
Arterial blood gases
Table 3
Symptoms and Signs in Patients with
Pulmonary Arterial Hypertension
Complete blood count
Sickle cell screen*
Fatigue
Jugular venous distention (c-v wave)
PTT (looking for anti-cardiolipin antibodies)
Breathlessness
Kussmaul’s sign
Coagulation screen*
Pre-syncope and
syncope
Loud pulmonic sound
Electrolytes, urea, creatinine, urinalysis
Chest pain
Right sided S3/S4
HIV serology
Forceful heart beat
Tricuspid/pulmonic insufficiency
Antinuclear antibodies
Leg and abdominal
swelling
Peripheral edema
Anti-histone antibodies (Ro, La, Scl-70, Jo)*
Cough*
Hepatomegaly
Change in voice*
Ascities
Liver function tests
* Possibly due to compression of recurrent laryngeal nerve from an
enlarged pulmonary artery.
32 GERIATRICS & AGING • November 2002 • Vol 5, Num 9
Pulmonary angiography*
Cardiac catheterization*
Sleep study*
* where indicated
Pulmonary Arterial Hypertension
a search for an intracardiac or pulmonary shunt must be performed. We
find that computed tomographic scanning of the chest with high-resolution
images is a critical tool. First, it is useful
for evaluating the presence or burden of
parenchymal lung disease. Second, it
is helpful for evaluating the presence of
less common forms of PAH, such as
veno-occlusive disease, which respond
poorly to therapy and may even worsen precipitously with the use of conventional vasodilator therapy. Finally,
characteristic ventilation-perfusion scan
findings generally exclude chronic
thromboembolic disease.
We commonly perform a right
heart catheterization in our patients. We
use the information to exclude secondary causes, such as left ventricular dysfunction, and evaluate the capacity of
the pulmonary vasculature to vasodilate. Significant prognostic information
including baseline cardiac output, mean
right atrial pressure and mixed venous
oxygen saturation can also be obtained.
Again, findings related to poor right
ventricular function, such as elevated
right atrial pressure and low mixed
venous saturation, portend a worse
prognosis.
Therapy
Treatment of PAH has two main
objectives:
1. In the setting of secondary PAH, therapy
must be directed at the underlying disorder.
2. Therapy is directed at reducing the pulmonary arterial pressures, improving right
ventricular pressure and preventing further
vascular injury.
Much of the literature regarding treatment comes from data obtained in
patients with primary PAH or those with
PAH associated with connective tissue
disease. Although PAH remains a common reason for referral for lung transplantation, the surgery is not performed
in patients with PAH who are over the
age of 60.This is due to the higher perioperative mortality and morbidity of
PAH patients compared with patients
undergoing transplantation for other
indications.9 Consequently, therapy for
PAH in the elderly rests on medical
strategies.
Therapy for Primary
Pulmonary Hypertension
Vasodilators
The rationale for therapy with vasodilators relates to the observed defects in
vasoregulation. The typical (and likely
becoming historic) class of vasodilators
are calcium channel blockers. Unfortunately, these medications may have a
significant effect on systemic blood
pressure and negative inotropic effects.
Only patients who demonstrate an
acute “response” during right heart
catheterization to inhaled or intravenous vasodilators are subsequently
challenged acutely with calcium channel blockers. Characteristic changes that
predict response to long-term oral calcium channel blocker therapy include a
reduction in pulmonary artery pressure
accompanied by an increase in cardiac
output, with little change in systemic
pressure or arterial oxygen saturation.10,11 However, the role of calcium
channel blockers as sole therapy needs
to be revisited. It is difficult to advocate
the use of calcium channel blockers
with the advent of newer oral therapies
and in the face of the methodological
quality of earlier studies of calcium
channel blockers.
Rationale for the use of prostacyclin
stems from the observation of a relative
reduction in prostanoids in patients
with PAH as well as from its role as a
short-acting vasodilator and inhibitor of
platelet aggregation. Long-term treatment with continuous intravenous
epoprostenol, a prostacyclin analog, has
demonstrated long-term beneficial outcomes including improvement in
hemodynamics, exercise tolerance and
survival in patients with both PPH and
SPH.12-14 Interestingly, the benefit of
epoprostenol has been found even in
patients who have no significant
response to acute vasodilator challenge.
This suggests that its mechanism of
action is beyond simply decreasing
vasomotor tone and is possibly due to
other properties that mediate vascular
remodeling.
Epoprostenol must be administered
continuously through a central venous
catheter. It is chemically unstable and
must be shielded from heat and light.
The requirements of administration and
the extensive side effects make it
impractical for many elderly patients.
Recently, a more stable analogue, UT-15
(Uniprost®, Remodulin™), has been
developed.15 Uniprost is administered
subcutaneously and does not require
daily admixture. Despite demonstration
of clinical benefit, significant pain at the
injection site from UT-15 has become a
severe limitation in its widespread use.
Inhalation of a prostacyclin analogue
called iloprost has recently been shown
to improve hemodynamics and functional status in patients with PAH.16
Unfortunately, owing to the short halflife of this medication, it must be
administered every four hours. In addition, it is not clear that the beneficial
hemodynamic effects extend beyond
the treatment intervals.
For the ideal treatment of PAH, one
should choose an agent that may be
taken orally, is selective for the pulmonary circulation and is well tolerated.
Endothelin receptor antagonists have
shown recent promise for the long-term
treatment of PAH. The rationale underlying their use is based on the observation of increased levels of endothelin in
patients with PAH.17 Endothelin has
been implicated in the pathogenesis of
PAH as it is a potent vasoconstrictor, a
mediator of smooth muscle cell growth
and differentiation and found in high
concentrations in the plexiform lesions
that characterize PAH. Controlled studies have demonstrated hemodynamic
improvement, increased exercise tolerance and improved survival over one
year in class III/IV patients with PPH
and SPH treated with the non-selective
endothelial receptor antagonist, bosentan.18,19 Unfortunately, this medication is
also extremely expensive, and liver toxicity (requiring dose adjustment or diswww.geriatricsandaging.ca 33
Pulmonary Arterial Hypertension
continuation in 10% of patients) limits its
use. In addition, the clinical experience
with bosentan is limited to two short clinical trials (12 and 16 weeks, respectively).
The long-term benefit of this agent
remains to be established.
Recent interest has focused on the
use of phosphodiesterase inhibitors. As
a class, these agents mediate vasodilation by decreasing the degradation of
cyclic-guanosine monophosphate
(cGMP). In particular, sildenafil (Viagra®) shows promise as a selective pulmonary vasodilator.20,21 A prospective
study, however, is still required before
one can embrace sildenafil as therapy
for PAH.
Inotropes
The rationale for treatment with inotropic agents in PAH is to increase cardiac
output. In patients with PPH and right
ventricular failure, digoxin has been
shown to have beneficial acute hemodynamic effects through an increase in cardiac output.22 The benefit to the patient
and long-term consequences of digoxin
are unknown. We currently reserve the
use of digoxin for those patients who
have moderate or worse right ventricular dysfunction.
Anticoagulation
The rationale for anticoagulant therapy
in patients with PAH is based on the
observations of in situ thrombosis, abnormalities in the coagulation cascade and
endothelial dysfunction in PAH.23,24
There are also concerns that co-existing
venous insufficiency and reduction in
physical activity imposed by the disease
may predispose to thromboembolism.
Anticoagulant therapy with warfarin has
been shown to improve survival in
patients with PPH with added survival
benefit when combined with a vasodilator.11 In general, the INR is maintained
between 2 and 2.5.
Other Supportive Measures
The reduction of excessive preload in
patients with right ventricular failure as
a consequence of PAH can be achieved
with diuretics and institution of a low-salt
34 GERIATRICS & AGING • November 2002 • Vol 5, Num 9
diet. Reduction in the degree of peripheral edema is often of symptomatic benefit to these patients. Oxygen, when
required, should be administered to
maintain saturation above 90%. In the
absence of valvular or structural heart
disease, patients do not require antibiotic prophylaxis for surgical procedures.
We encourage an active lifestyle within
limits of their symptoms. Deconditioning
will only lead to further disability.
Patients are cautioned to avoid sudden
increases in activity, straining or environments that may lead to excessive peripheral vasodilation.
Targeted Therapeutic Modalities
in Secondary Pulmonary
Hypertension
Treatment of SPH is directed by management of the underlying disease. In
patients with left ventricular dysfunction, treatment considerations include
digoxin, diuretics and afterload reducing agents. The most important factor in
PAH associated with chronic obstructive pulmonary disease is alveolar
hypoxia. The approach to therapy is to
optimize lung function and gas
exchange with bronchodilators and
steroids. If hypoxemia persists after one
month of treatment, then long-term
continuous home oxygen is indicated.
It is clear that continuous use of oxygen
in patients who have a PaO2 less than
60mmHg and PAH will experience an
improvement in survival and pulmonary pressures. 25 The role of
vasodilator therapy in patients with coexisting pulmonary parenchymal disease is unclear. Indeed, there is a
significant concern that there is a potential for detriment owing to worsening of
hypoxemia due to increased ventilation/perfusion mismatch. In patients
with collagen vascular disease, a trial of
corticosteroids or other immunosuppressive agents are occasionally prescribed to see if there is a reversible
inflammatory component to the PAH.
Surgery (pulmonary thromboendarterectomy) for accessible chronic
thromboemboli is potentially curative. 26,27 Patients for this procedure
must be carefully selected based not
only on the location of the thrombosis
but also on careful assessment of limiting comorbidities that may impact
upon outcome. At present, only scattered specialized centres perform this
procedure.
Conclusion
Advances in the understanding of the
pathophysiology of PAH have led to the
development of therapies that are capable of improving quality of life and life
span in patients. Predictors of survival in
PPH include severity of disease as measured by hemodynamic status, functional
class, exercise tolerance, use of anticoagulant therapy and response to vasodilators.
Patients
who
respond
symptomatically and hemodynamically
to directed therapy have the best prognosis.28 Although studies evaluating the
pathogenesis of PAH and response to
therapy in the elderly are lacking, with
the advent of oral medications, the
prospects for the elderly patient with
PAH have improved.
◆
Dr. Granton has acted as a consultant
and will be receiving funding for a clinical
trial from Actelion, the maker of bosentan.
Dr. Zafar has declared no competing
financial interests.
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