“… The pulmonary circulation in patients with chronic pulmonary disease is often considered a no-man`s land, falling between the domains of the respirologist and the cardiologist and understood only by the physiologist!” (1).
Classification of Pulmonary Hypertension
Pulmonary hypertension was previously divided into primary and secondary categories;
primary pulmonary hypertension described an idiopathic hypertensive vasculopathy,
exclusively affecting pulmonary circulation, whereas secondary pulmonary hypertension
was associated with a causal underlying disease process (2, 3). The diagnosis
of primary pulmonary was one of exclusion after ruling out all causes of pulmonary
hypertension (4). The recent identification of a gene responsible for the inherited
forms of this disease, along with the development of specific medical treatments
and the refinement of surgical techniques, has prompted a revised classification
of pulmonary hypertension (5). In 2003, Third World Symposium on pulmonary arterial
hypertension held in Venice – Italy decided to maintain the general architecture
and philosophy of the Evian – France classification (1998) and to propose some
modifications. The aim of the modifications was to make the “Venice clinical
classification” more comprehensive, easier to follow and widespread as a tool
(4) (
Table 1).
Table 1.
Clinical classification of Pulmonary Hypertension (PH) – Venice 2003. |
|
Modified from Simonneau
G, Galie N, Rubin LJ et al. J Am Coll Cardiol 2004; 43: 5S-12S. |
Definition and clinical symptoms
Pulmonary arterial hypertension is defined as a group of diseases characterized by a progressive increase of pulmonary vascular resistance leading to right ventricular failure and premature death (6). Pulmonary hypertension is defined by a mean pulmonary arterial pressure over 25 mmHg at rest or over 30 mmHg during activity with accompanying increase of pulmonary vascular resistance over 3 WU (Wood`s unit) (2).
In its early stages pulmonary arterial hypertension may be asymptomatic. Pulmonary hypertension often presents with nonspecific symptoms. The most common symptoms – exertional dyspnea, fatique, and syncope – reflect an inability to increase cardiac output during activity. The leading symptom of pulmonary arterial hypertension is exertional dyspnea. A minority of patients may report typical angina despite normal coronary arteries. The symptoms of pulmonary hypertension can also include weakness and abdominal distension (7). Hemoptysis resulting from the rupture of distended pulmonary vessels is a rare but potentially devastating event. Raynaud`s phenomenon occurs in approximately 2% of patients with primary pulmonary hypertension, but it is more common in patients with pulmonary hypertension related to connective tissue disease. More specific symptoms may reflect the underlying cause of pulmonary hypertension (8). Symptoms at rest are reported only in very advanced cases.
Etiology and pathophysiology
The estimated incidence of primary pulmonary hypertension is 1-2 cases per 1 million persons in the general population. Pulmonary hypertension is more common in women than in men (ratio: 1.7 to 1) (9). Pulmonary hypertension is most prevalent in persons 20 to 40 years of age (3). In persons more than 50 years of age, cor pulmonale, the consequence of untreated pulmonary arterial hypertension, is the third most common cardiac disorder (after coronary and hypertensive heart disease) (9, 10). Mean life time expectancy from the time of diagnosis in patients with idiopathic pulmonary arterial hypertension, before the availability of disease-specific targeted therapy, was 2.8 years (4).
Normal pulmonary artery systolic pressure at rest is 18 to 25 mmHg, with a mean pulmonary pressure ranging from 12 to 16 mmHg. This low pressure is due to the large cross-sectional area of the pulmonary circulation, which results in low resistance (9).
The exact processes that initiate the pathological changes seen in pulmonary
arterial hypertension are still unknown, even if we now understand more of the
mechanisms involved. It is recognized that pulmonary arterial hypertension has
a multi-factoral pathophysiology that involves various biochemical pathways
and cell types. The increase of pulmonary vascular resistance is related to
different mechanisms including vasoconstriction, obstructive remodelling of
the pulmonary vessel wall, inflammation and thrombosis. Pulmonary vasoconstriction
is believed to be an early component of the pulmonary hypertensive process (11).
In the pulmonary circulation, there is a homeostatic balance between a variety
of mediators that influence vascular tone, cellular growth and coagulation.
In pulmonary arterial hypertension, pulmonary endothelial cell dysfunction or
injury promotes the pathological triad of vasoconstriction, cellular proliferation
and thrombosis through the action of mediators such as thromboxane A
2,
endothelin-1 and serotonin. Under normal circumstances, these effects are counterbalanced
by prostacyclin, vasoactive intestinal peptide and nitric oxide, which tend
to have opposite effects (12, 5). Irrespective of the underlying etiology of
pulmonary arterial hypertension, the histological appearance of lung tissue
in each of these conditions is similar and consists of intimal fibrosis, increased
medial thickness, pulmonary arteriolar occlusion and plexiform lesions (5).
The process of pulmonary vascular remodelling involves all layers of the vessel
wall and is characterised by proliferative and obstructive changes that involve
several cell types including endothelial, smooth muscle and fibroblasts (13).
Diagnostics
The clinical cardinal symptom of pulmonary hypertension is dyspnea. The diagnostic
process of pulmonary hypertension requires a series of investigations that are
intended to make the diagnosis, to clarify the clinical class of pulmonary hypertension
and the type of pulmonary arterial hypertension and to evaluate the functional
and hemodynamic impairment (
Table 2).
Table 2.
Diagnosis of pulmonary hypertension. Clinical classification: WHO/NYHA. |
|
Non-invasive diagnostics
Functional assessment. Patients with pulmonary hypertension can be classified
according to their ability to function, modified from the New York Heart Association
classification of patients with cardiac disease (
Table 3).
Table 3.
Modified NYHA-classification in pulmonary hypertension. |
|
Hoeper M, Oudiz R, Peacock
A et al. J Am Coll Cardiol 2004; 43: S48-S55. |
Physical examination. Physical examination can reveal increased jugular
venous distention, a tricuspid regurgitant holosystolic murmur and a loud P2,
all suggestive of elevated right-sided pressure. Lung sounds are usually normal.
Hepatomegaly, peripheral oedema, ascites and cool extremities characterize patients
in a more advanced state with right ventricular failure at rest.
Electrocardiography. Electrocardiographic signs of the right heart compromise
include right axis deviation, right ventricular hypertrophy, and peaked P waves.
However, the electrocardiography lacks sufficient diagnostic accuracy to serve
as a screening tool for the detection of pulmonary arterial hypertension. Right
ventricular hypertrophy on ECG is present in 87% and right axis deviation in
79% of patients (7). ECG has inadequate sensitivity (55%) and specifity (70%)
(14). A normal ECG does not exclude the presence of severe pulmonary hypertension.
Chest radiography. The chest radiograph is inferior to ECG in detecting
pulmonary hypertension, but it may show evidence of underlying lung disease
(15). In 90% of pulmonary arterial hypertension patients the chest radiograph
is abnormal at the time of diagnosis (7). The finding include central pulmonary
arterial dilatation which contrasts with “pruning” of the peripheral blood vessels.
A hilar-to-thoracic ratio greater than 0.44, a right descending pulmonary artery
diameter of greater than 18 mm and right atrial and ventricular enlargement
may be seen and it progresses in more advanced cases. However, a normal chest
radiograph does not exclude mild pulmonary hypertension including left-heart
disease or pulmonary veno-occlusive disease.
Echocardiography. Transthoracic echocardiography is an excellent non-invasive
screening test for the patient with suspected pulmonary hypertension. Transthoracic
echocardiography estimates pulmonary artery systolic pressure and can provide
additional information about the causes and consequences of pulmonary hypertension.
Pulmonary artery systolic pressure is equivalent to right ventricular systolic
pressure in the absence of pulmonary outflow obstruction. With CW-Doppler-echocardiography
right ventricular systolic pressure (RVSP) can be obtained by adding the estimated
right atrial pressure (RAP) to the pressure gradient derived from systolic regurgitant
tricuspid flow velocity v according the formula: RVSP = 4
v2
+ RAP. Echocardiographic estimation of the right atrial pressure by measuring
the diameter of the inferior vena cava and the respiratory motion of the inferior
vena cava (
Table 4). According to the normal ranges of Doppler-derived
values of pulmonary artery pressures, mild pulmonary hypertension can be defined
as pulmonary artery systolic pressures of approximately 36-50 mmHg or resting
tricuspid regurgitant velocity of 2.8-3.4 m/sec assuming a normal right atrial
pressure of 5 mmHg. The right ventricular systolic pressure may be underestimated
in some cases because of suboptimal tracings of the regurgitation jet, of decreased
tricuspid regurgitant jet velocity due to high right atrial pressures, and poor
estimation of right atrial pressures. However, in order to estimate a right
ventricular systolic pressure by echocardiography, tricuspid regurgitation must
be present.
Table 4.
Echocardiographic estimation of the right atrial pressure (RAP) by measuring
the diameter of the inferior vena cava and the respiratory motion of the
inferior vena cava inferior (VCI). |
|
Indirect signs of pulmonary hypertension are: paradoxical septal motion (septal bowling or flattering), decreased or missing collapse of the vena cava inferior, pericardial effusion, right ventricular hypertrophy and reduced right ventricular ejection time. Additional examination to the routine echocardiography is the estimation of right ventricular Tei-index (isovolumetric contraction time and relaxation time/ejection time) (24) and the “tricuspid annular plane systolic excursion” (TASPE). The peak early diastolic pulmonary regurgitation velocity is useful in estimating mean pulmonary artery pressure (mean PAP). Together with the dimension of the right atrium and pericardial effusion Tei-index and TASPE are important prognostic parameters in patients with pulmonary hypertension, while the right ventricular systolic pressure does not correlate with survival (16). Echocardiography is the most useful imaging modality for detecting pulmonary hypertension and excluding underlying cardiac disease.
Serology and biomarkers. All patients with suspected or documented pulmonary
hypertension should undergo serologic testing Initial laboratory evaluation
includes a complete blood count, prothrombin time, hepatic profile, and serologic
studies for collagen vascular disease suggested by history or physical examination.
Special autoantibodies might include antinuclear and anti-DNA (systemic lupus
erythematosus), anti-Scl-70 and antinuclear (scleroderma), anticentromere (CREST
syndrome), rheumatoid factor (rheumatoid arthritis), anti-Ro and anti-La (Sjogren`s
syndrome), anti-Jo-1 (dermatomyositis/polymyositis) and anti-U1 RNP (mixed connective
tissue disease). HIV testing should be considered in all patients, especially
those with a compatible history or risk factors.
The use of plasma brain natriuretic peptide (BNP) is well established in the
diagnosis and staging of patients with congestive heart failure. Recently, measurement
of BNP has been shown to be a useful prognostic tool in the population of patients
with primary pulmonary hypertension (17) and chronic lung diseases (18). It
has been shown, that plasma BNP levels is associated with pulmonary artery pressure
and pulmonary vascular resistance. Further on, there is a correlation of exercise
parameters (VO
2 peak, WHO functional class,
6-minute walk). Additionally, alterations in n-terminal pro BNP reflect changes
in right ventricular structure and function in pulmonary hypertension patient
during treatment (19). Therefore, BNP seems to be a simple, non-invasive tool
and observer independent parameter for assessing disease severity and treatment
efficiency in patients with pulmonary hypertension.
Ventilation/Perfusion Scanning. Ventilation/perfusion scans are often
used to rule out other causes of dyspnea. Fortunately, ventilation-perfusion
lung scanning is a reliable method for differentiating chronic thromboembolism
from primary pulmonary hypertension (9). Normal ventilation and quantification
scans rule out chronic thromboembolic disease (20). The finding of one or more
segmental or larger perfusion defects is a sensitive marker of embolic obstruction.
Computerized tomography. Computerized tomographic (CT/MRI) scanning of
the chest with high-resolution images is useful to exclude occult interstitial
lung disease and mediastinal fibrosis. It also is helpful in diagnosis of pulmonary
embolism. Magnetic resonance imaging can be used to assess the size and function
of the right ventricle, myocardial thickness, the presence of chronic thromboembolic
disease with a mosaic pattern of the lung parenchyma and cardiac and pulmonary
pressures (21, 22).
Pulmonary Function Testing. The role of pulmonary function testing is
to rule out parenchymal or obstructive lung disease as the cause of the patient`s
symptoms. Unless hypoxia is present, pulmonary hypertension cannot be attributed
to these disorders until pulmonary function is severely reduced. Some patients
with pulmonary artery hypertension can have a mild decline in their total lung
capacity and diffusing capacity for carbon monoxide, but the severity of these
declines do not correlate with disease severity. With pulmonary function testing
neither an accurate diagnosis nor adequate follow-up examinations are possible.
Six-minute walk test. Submaximal testing with a 6-minute walk test is
recommended at the time of diagnosis to establish baseline functional impairment
and at the follow-up to assess response to therapy and prognosis (21). The mortality
risk is increased 2.4-fold in patients with pulmonary arterial hypertension
who are able to walk less than 300 m in 6 minutes and 2.9-fold in those with
a greater than 10% decline in arterial oxygen saturation (23). The 6-minute
walk distance correlates with severity by NYHA functional class in patients
with pulmonary hypertension, and patients who walk less than 332 m have a significantly
lower survival rate than those who walk farther (24).
Cardiopulmonary Exercise Testing. Cardiopulmonary exercise testing (CPET)
allows measurement of ventilation and pulmonary gas exchange during exercise
testing providing additional “pathophysiologic” information to that derived
from standard exercise testing. Cardiopulmonary exercise testing has no added
value in the initial diagnostic testing of pulmonary hypertension. The most
important parameters are the maximal oxygen uptake (peak VO
2)
and the relation from ventilation to CO
2-relief
(V
E/VCO
2). Pulmonary
hypertension patients show reduced peak O
2,
reduced peak work rate, reduced ratio of VO
2
increase to work rate increase, reduced anaerobic threshold and reduced peak
oxygen pulse; they show also increased V
E and
VCO
2 slope representative of ventilatory inefficiency
(25).
Invasive diagnostics
Right Heart Catheterization. Right heart catheterization remains the
gold standard for the diagnosis of pulmonary hypertension. All patients suspected
of having significant pulmonary hypertension after clinical and transthoracic
echocardiographic evaluation should undergo right heart catheterization, particularly
if they are candidates for treatment (21).
The modern era in cardiopulmonary medicine began in the 1940s, when Cournand
and Richards pioneered right-heart catheterization. Right-heart catheterization
ignited an explosion of insights into function and dysfunction of the pulmonary
circulation, cardiac performance, ventilation-perfusion relationships, and lung-heart
interactions. Right heart catheterization is the only method for direct proof
of an increased pressure in the pulmonary circulation system. Cardiac catheterization
gives information about the heart, because it is the limiting organ for performance
and prognosis of pulmonary hypertension! The goals of right heart catheterization,
in addition to making the diagnosis, are to measure right atrial and ventricular
pressures, to detect pulmonary artery pressure (PAP systolic, PAP diastolic,
PAP mean) and pulmonary artery capillary wedge pressure (PCWP), to measure pulmonary
vascular and systemic vascular resistance (PVR, SVR), to calculate cardiac output/index
(end organ function) by Fick principle or thermodilution, to evaluate pulmonary
artery O
2-saturation, and to look for the presence
of left-to-right shunts and right-to-left shunt (the latter makes left heart
cardiac catheterization necessary). The significance of right heart catheterization
is to assess the severity of the hemodynamic impairment, to predict the prognosis,
to identify other causes of pulmonary hypertension, to monitor the etiopathology,
to evaluate the right ventricular function, and to test the vasoreactivity of
the pulmonary circulation.
Vasodilator testing during right-heart cardiac catheterization should only be done using short-acting vasodilators such as adenosine/epoprostenol intravenously, prostacyclin, nitric oxide or iloprost by inhalation. According to the European Society of Cardiology, a response to acute vasodilator testing includes a decrease of more than 10 mmHg in the mean pulmonary artery pressure and/or a decrease of the mean pulmonary artery pressure under 40 mmHg. Responders to acute vasodilator testing have a favorable clinical response and course when treated with calcium channel blockers, but calcium channel blockers should be strictly avoided in non-responders. There are no absolute contraindications to right heart catheterization and complications are rare, although may happen.
Disease monitoring
While echocardiography is the screening method for acquisition of pulmonary
hypertension (high sensitivity), the right heart cardiac catheterization has
a higher specificity and is a required method to confirm the diagnosis definitely
(
Table 5). Some patients with mild and moderate pulmonary hypertension
can be managed without right heart catheterization. Those with mild to moderate
pulmonary hypertension due to chronic hypoxemia (resting, exertional or noctural)
can be followed with serial echocardiography for evidence of progression on
appropriate oxygen and/or noctural ventilatory support. For patients with mild
to moderate pulmonary hypertension by echocardiography who do not have NYHA
class III symptoms, right heart cardiac catheterization can be reserved as a
future option if pulmonary hypertension progresses on serial echocardiography
every 3 to 6 months.
Table 5.
Pulmonary hypertension (PH): Diagnostic approach. |
|
Right heart function and ejection fraction have a great importance in patients
with pulmonary hypertension: clinical severity and mortality rate do increase
in concert with the degree of limitation of the right ventricular function and
ejection fraction. The higher the mean pulmonary arterial pressure and the pulmonary
wedge pressure and the worse the right ventricular function, the higher the
mortality with left heart insufficiency will be. Patients with a low ejection
fraction and high pulmonary artery pressure show a particularly bad prognosis,
independent from the degree of restricted left ventricular function (26) (
Table
6).
Table 6.
Estimation of prognosis in pulmonary hypertension (PH). |
|
Conclusion
Pulmonary hypertension is defined as an elevation in pulmonary arterial pressures and is characterized by symptoms of dyspnea, chest pain and syncope. If untreated, pulmonary arterial hypertension has a high mortality rate, typically from decompensated right-sided heart failure. Estimated median survival is approximately 2.8 years.
The past decade has seen major advances in our understanding of the pathophysiological mechanisms underlying the development of pulmonary arterial hypertension. The diagnosis is now more clearly defined according to a new clinical classification, and clear algorithms have been devised for the investigation. However, the prognosis of pulmonary arterial hypertension remains guarded despite recent advances and new therapeutic options.
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