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Pulmonary arterial hypertension: Monitoring the patient’s
response to therapy, part 1
October 01, 2009 | Journal Of Respiratory Diseases [1]
By James R. Klinger, MD [2]
Careful monitoring of disease progression is vital to ensuring that patients with pulmonary arterial
hypertension receive maximal therapy before the onset of overt right-sided heart failure. Routine
follow-up includes the evaluation of symptoms, functional class, and exercise capacity and
assessment of pulmonary pressures and right ventricular (RV) function. Transthoracic
echocardiography (TTE) offers a noninvasive and fairly reliable technique for monitoring pulmonary
artery pressure (PAP) and structural changes of the right side of the heart. However, TTE does not
reliably assess cardiac output, right-sided filling pressures, or pulmonary venous pressure.
Pulmonary artery catheterization may be particularly useful in patients who have inconsistent
findings, such as a reduction in PAP measured by TTE in the presence of worsening symptoms or
other signs of disease progression. An increase in RV end-diastolic pressure, usually above 10 mm
Hg, is a concern and warrants consideration of additional therapy even if other hemodynamic and
clinical parameters are unchanged. (J Respir Dis. 2009;30(1-2)
ABSTRACT: Careful monitoring of disease progression is vital to ensuring that patients with
pulmonary arterial hypertension receive maximal therapy before the onset of overt right-sided heart
failure. Routine follow-up includes the evaluation of symptoms, functional class, and exercise
capacity and assessment of pulmonary pressures and right ventricular (RV) function. Transthoracic
echocardiography (TTE) offers a noninvasive and fairly reliable technique for monitoring pulmonary
artery pressure (PAP) and structural changes of the right side of the heart. However, TTE does not
reliably assess cardiac output, right-sided filling pressures, or pulmonary venous pressure.
Pulmonary artery catheterization may be particularly useful in patients who have inconsistent
findings, such as a reduction in PAP measured by TTE in the presence of worsening symptoms or
other signs of disease progression. An increase in RV end-diastolic pressure, usually above 10 mm
Hg, is a concern and warrants consideration of additional therapy even if other hemodynamic and
clinical parameters are unchanged.
Pulmonary arterial hypertension (PAH) is a disease of the pulmonary arterial tree that results in
progressive remodeling and obliteration of the small pulmonary arterioles leading to right ventricular
(RV) failure and usually death.1 Although the disease may affect anyone, it is more common in
women and often affects young, otherwise healthy persons.2
The devastating effects that PAH has on function and survival have led to an intensive research
effort during the past 25 years that has provided intriguing insight into numerous cellular and
molecular pathways that are important in pulmonary vascular remodeling. One of the greatest
accomplishments has been the identification of a single genetic defect that appears to be present in
nearly half of all sporadic cases of PAH and in almost three-quarters of familial cases, providing hope
that one day a cure for this tragic disease may be found.3-5
In the meantime, therapies have been developed that slow disease progression and improve
survival. Several reviews describing the safety and efficacy of available therapies have proposed
treatment algorithms that guide drug selection on the basis of patient characteristics and disease
severity (Figure 1).6-8 Implicit in these treatment protocols is the idea that patients should be closely
monitored for response to therapy and that therapy should become more aggressive if there is
evidence of disease progression.
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Footnote to figure 1:
a
Strength of ACCP recommendation: A, strong; B, moderate; C, weak; E/A, strong based on expert
opinion only; E/B, moderate based on expert opinion only; E/C, weak based on expert opinion only.
b
In patients in World Health Organization functional class II or III, oral therapy can be started with an
endothelin receptor antagonist or a phosphodiesterase inhibitor. Patients in a more advanced
functional class may require prostacyclin or combination therapy. Patients who present with or
progress to the worst functional class (class IV) should be given intravenous prostacyclin infusion.
c
Not in order of preference.
PAH, pulmonary arterial hypertension; IPAH, idiopathic PAH; ACCP, American College of Chest
Physicians.
Adapted from Badesch DB et al. Chest. 2007.7
The purpose of this 2-part article is to review the currently available methods for assessing disease
severity in patients with PAH and monitoring patient response to therapy. Despite important
therapeutic advances, PAH remains an incurable disease and few patients will experience
normalization of pulmonary hemodynamics or exercise function. Thus, early identification of disease
progression is vital in maximizing patient response to therapy.
OVERVIEW
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Pulmonary hypertension is defined as increased pressure in the arterial side of the pulmonary
circulation. Normally, the pulmonary circulation is a low-pressure, high-flow vascular bed. Marked
increases in blood flow that occur during strenuous exercise are accommodated by vasodilation and
the recruitment of underfilled vessels, resulting in a fall in pulmonary vascular resistance (PVR) and
little rise in pulmonary artery pressure (PAP). Similarly, the right ventricle is a highly compliant,
low-pressure pump that is well designed for accommodating large increases in right-sided filling
volumes but is intolerant of sudden increases in afterload.
Elevation of PAP in PAH is the result of increased pulmonary vascular tone and extensive remodeling
of pulmonary arteries and arterioles.9 Structural and functional changes of the pulmonary arterial
circulation result in significant reduction of the total pulmonary vascular luminal area and loss of the
normal vasodilatory responses to increased flow. The PAP and PVR are elevated at rest and rise
further during exercise. As RV afterload increases, RV systolic function declines, the right ventricle
dilates, and cardiac output begins to fall (Figure 2). Patients begin to have clinical manifestations of
right-sided heart failure and become progressively more intolerant of exercise.
Figure 2 – The hemodynamic changes associated with disease progression in patients with
pulmonary arterial hypertension are illustrated here. Pulmonary artery pressure (PAP) and
pulmonary vascular resistance (PVR) rise while patients are asymptomatic. Further elevation in
resistance causes symptoms of exercise limitation, but cardiac output (CO) at rest is maintained. In
the final stages, PAP may fall even as PVR increases as a result of declining right-sided heart
function. The fall in right ventricular systolic function and CO is often heralded by a rise in right
ventricular end-diastolic pressure and right atrial pressure (RAP). (Adapted from Hill NS. In: Hill NS,
ed. Pulmonary Hypertension Therapy. 2006.28)
Medical therapy for PAH in the United States currently consists of 3 classes of drugs: prostacyclin
analogues, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors. Three different
prostanoid preparations are available, which allows treatment to be administered by continuous
intravenous or subcutaneous infusion or intermittent inhalation (Table 1). Two endothelin receptor
antagonists are available. Bosentan, which is a nonselective endothelin receptor antagonist, has
similar affinity for both endothelin A-type (ETA) and B-type receptors, whereas ambrisentan is highly
selective for ETA. Sildenafil and, more recently, the longer-acting tadalafil are the phosphodiesterase
type 5 inhibitors approved for the treatment of PAH.
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No large randomized clinical trials have compared the efficacy or safety of any class of drug with
that of another. However, the clinical experience of most practitioners is that endothelin receptor
antagonists and phosphodiesterase type 5 inhibitors have similar efficacy and that continuous
prostanoid infusion is superior to either. The strong sentiment among practitioners who treat
patients who have PAH that prostanoid infusion therapy is superior to oral therapy with either an
endothelin receptor antagonist or a phosphodiesterase type 5 inhibitor is demonstrated by
algorithms published by several professional societies to guide the treatment of PAH.6-8 These
guidelines recommend that patients with early PAH who have minimal to moderate symptoms
without right-sided heart failure be given oral therapy with either an endothelin receptor antagonist
or a phosphodiesterase type 5 inhibitor or inhaled prostacyclin. Patients who present with or who
progress to the worst functional class are treated with intravenous prostacyclin.
The dilemma faced by most physicians treating patients with PAH is how to determine when the
inconvenience, expense, and adverse effects of continuous infusion therapy are justified by the
severity of disease progression. To properly address this challenge, the practitioner must be able to
reliably determine when a patient with PAH is improving, has stabilized, or is deteriorating.
MONITORING RESPONSE TO THERAPY
History and physical examination
The greatest advantage of these often overlooked tools for monitoring disease progression is their
ability to be used repeatedly with minimal expense and no harm to the patient. The timeline for
progression in PAH can be as short as several weeks to months. Indeed, in some clinical trials,
patients with PAH randomized to receive placebo had significant declines in functional capacity,
including several deaths in as little as 12 weeks.10
Therefore, most patients who require medical therapy for PAH should be examined frequently until
the physician is confident that they are improving or that their disease has remained stable. In our
center, patients with PAH are seen every 4 weeks for the first 6 months and every 6 to 12 weeks
thereafter, if their disease appears to be controlled.
The history taking should focus on the patients' perception of their functional capacity. Patients who
were fairly active should be able to report that they can do more, have more energy, or can do
previous activities faster or with less dyspnea than before starting therapy. Patients who were more
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incapacitated by PAH may report increased mobility at home, less difficulty with activities of daily
living, and decreased fatigue. One problem practitioners may face in trying to ascertain
improvement in functional capacity is the generally low level of activity that many persons have
before they become ill.
As described above, the pulmonary circulation is designed to maintain low resistance even under
high-flow states. Early symptoms of PAH are limited almost entirely to those that occur with exertion.
Dyspnea, chest pain, and light-headedness occur during stressful activity well before they occur with
ordinary activity or at rest. The World Health Organization (WHO) revision of the New York Heart
Association functional classification is designed to assess disease severity on the basis of the level of
activity required to produce symptoms (Table 2). However, unless patients attempt more than
ordinary activity, it can be difficult to determine their true functional class. Frequently, patients are
asked whether they have difficulty in walking up an incline, climbing stairs, or carrying heavy
objects, but many have learned to avoid these activities or to perform them slowly enough not to
induce symptoms.
The subjective quality of the WHO functional classification has limited its usefulness in monitoring
disease progression in individual patients. In particular, patients can have considerable disease
progression as they move from early class III to late class III, causing some physicians to divide these
patients into class IIIA and IIIB. These designations are entirely subjective and depend on each
practitioner's interpretation. In general, a favorable response to therapy should result in a decrease
in at least 1 functional class—for example, from WHO class IV to III or from III to II.
The physical examination can provide more objective data for monitoring. Distention of the internal
jugular vein can be measured in centimeters above the clavicle and provide a reasonable estimate of
right-sided filling pressures. Weight gain should be measured carefully, accounting for differences in
scales and clothing. Hepatomegaly can be assessed by percussing the liver or by the number of
centimeters the liver is displaced below the costal margin.
The intensity of the pulmonic component of the second heart sound (heard best at the second
intercostal space of the left sternal border), the RV impulse, and the degree of lower extremity
edema are more operator-dependent but should be noted and recorded as carefully as possible. A
decrease in systemic blood pressure can occur with worsening right-sided heart function and is often
accompanied by an increase in resting heart rate.
The greatest limitation of the physical examination is that it is best at detecting evidence of RV
failure—a late finding in PAH. More sensitive measures of disease progression are usually needed to
determine the optimal time to intervene with increased medical therapy.
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Chest radiograph and ECG
Posteroanterior and lateral chest radiographs provide fairly good information about RV size and can
detect enlargement of proximal pulmonary arteries. A baseline radiograph is important for excluding
acute or chronic lung disease and may present findings suggestive of chronic thromboembolic
disease or pulmonary venous hypertension resulting from left-sided heart disease or pulmonary
veno-occlusive disease. However, its ability to detect moderate changes in pulmonary
hemodynamics or early signs of RV dysfunction is fairly limited.
ECG evidence of RV hypertrophy or strain is not uncommon in patients who have PAH. One study
found right axis deviation in about three-quarters of the patients studied.11 Less common findings
included a qR and rSR′ pattern in V1, T-wave inversion inferiorly, ST-T segment depression in the
precordial leads, and complete right bundle-branch block. An ECG is important in the initial
evaluation of patients with PAH and should be repeated at least annually, but it is usually not helpful
in detecting gradual disease progression.
Echocardiography
Echocardiography has played a major role in the rapid growth in the diagnosis and monitoring of PAH
over the past 20 years. This rapid, noninvasive imaging technique can be performed almost anytime
with virtually no risk to the patient. Ultrasonic images attained using current technologies provide
clear 2-dimensional images of the atria and ventricles in most patients, revealing important
information on right atrial (RA) and RV size and function. Doppler ultrasonography allows reasonable
estimates of peak RV systolic pressure by measuring the speed of the tricuspid regurgitant jet and
using a modification of the Bernoulli equation: RV systolic pressure = 4(tricuspid regurgitant
velocity)2 + RA pressure.
In the absence of a significant pulmonary stenosis or insufficiency, RV and pulmonary artery systolic
pressures (sPAP) are considered to be equal. The RA pressure (RAP) cannot be measured by
echocardiography and is usually assigned an estimated value of 5 to 15 cm H2O, depending on the
size of the right atrium or the degree of inferior vena cava collapse during inspiration. In one study,
RAP was estimated to be 5, 10, or 15 cm H2O depending on whether inferior vena cava collapse
during inspiration was complete, partial, or absent.12 However, some investigators have found that
estimated RAP does not improve the accuracy of PAP measured by echocardiography, and some
echocardiography laboratories choose to report RV systolic pressure alone.13
Pulmonary artery diastolic pressure can also be estimated by measuring the velocity of the
pulmonary insufficiency jet at end-diastole. However, this measurement has not been as readily
adopted by most practitioners because the Doppler envelope of the pulmonary insufficiency jet can
be difficult to obtain.
Transthoracic echocardiography (TTE) estimates of PAP have been reported to correlate well with
measurements obtained at catheterization. However, measurements within any individual may vary
considerably. Chow and associates14 found an excellent correlation (r = 0.90) between sPAP
measured by TTE and right heart catheterization in 28 patients with chronic thromboembolic
pulmonary hypertension, but the difference in individual measurements in many patients was
significant (standard error of the estimate, 11.5 mm Hg).
Part of the discrepancy between PAP measurements may be the lack of simultaneous recording.
Berger and associates13 found a mean difference in sPAP of less than 5 mm Hg when TTE was done
at the same time as right heart catheterization in 69 patients who were being evaluated for a variety
of pulmonary hypertensive diseases. However, in a study of 81 patients with PAH who were treated
with epoprostenol, sPAP measured by TTE within 24 hours of catheterization was 11 ± 2 mm Hg
lower on average, and it was 20 mm Hg lower in 31% of the patients.15
Transesophageal echocardiography (TEE) provides better visualization of posteriorly located cardiac
structures, such as the left atrium and mitral valve, but it has not been shown to be superior to TTE
for the estimation of sPAP. In one report of patients with advanced lung disease who had been
studied before lung transplant, 20% of patients who had an sPAP of 45 mm Hg or higher during right
heart catheterization had an sPAP of less than 35 mm Hg when measured by TEE.12 Thus, although
echocardiography provides a useful assessment of sPAP, measurements should be confirmed by
pulmonary artery catheterization at the time of initial diagnosis and whenever these measurements
fail to agree with the clinical assessment of pulmonary hemodynamics.
In addition to estimating PAP, echocardiography provides important information about left-sided
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heart function and pulmonary venous pressure. Elevated PVR impedes pulmonary blood flow and
reduces left ventricular filling. Left atrial enlargement is distinctly unusual in patients with PAH, and
its presence should prompt further investigation to exclude left-sided heart disease, mitral valve
disease, or an atrial septal defect.
Serial measurements of PAP, RV and RA size, and RV contractility greatly aid in determining disease
progression in patients. As mentioned above, a fall in peak PAP may not always reflect a decrease in
PVR, but when seen in combination with a decrease in RV and RA size and improved RV contractility,
it is highly likely that the patient is improving.
Reliable estimation of RV ejection fraction (RVEF) is difficult to attain with 2-dimensional
echocardiography. Ultrasonography provides only 2-dimensional images, making it impossible to
accurately measure RV end-systolic and end-diastolic volumes. Fractional shortening, derived from
the differences in end-systolic and end-diastolic diameters, has been used as an index of RVEF, but
the unique geometry of the right ventricle makes it difficult to consistently repeat measurements
from the same area.
Other measurements have been developed that provide reasonable estimates of RV performance.
The Doppler RV index, or Tei index, is calculated by dividing the sum of isovolumetric contraction
and isovolumetric relaxation times by ejection time (defined as duration of pulmonic outflow).16 As
RV function declines, this index increases. The Doppler RV index has been shown to be higher in
patients with PAH than in healthy controls and to be an independent predictor of mortality.17
Conversely, RV size measured by echocardiography has been shown to decrease in patients who had
favorable responses to calcium channel blockers, prostacyclin, lung transplant, or
thromboendarterectomy.18-21 An adequate tricuspid regurgitant jet for measuring RV pressure is
detectable in more than 80% of patients with PAH, although some series have reported failure rates
as high as 40% to 70%.13-15,22
Overall, TTE offers a safe, noninvasive, and fairly reliable technique for monitoring PAP and
right-sided heart structural changes in patients undergoing treatment for PAH. However, its inability
to reliably assess cardiac output, right-sided filling pressures, and pulmonary venous pressure makes
it inadequate as a single test for monitoring disease progression. In particular, patients who have a
reduction in the peak PAP measured by TTE but have worsening symptoms or other signs of disease
progression require further evaluation, usually with pulmonary artery catheterization.
Pulmonary artery catheterization
The morbidity and mortality of PAH is caused by impaired blood flow through the pulmonary
circulation, which, in turn, is determined by RV output and PVR. Right heart and pulmonary artery
catheterization has been the gold standard for assessing disease severity in PAH patients because it
can most accurately measure both pressure and flow. In addition, pulmonary artery catheterization
provides accurate measurements of other hemodynamic variables, such as cardiac output, RAP, and
RV end-diastolic pressure, that have been found to be better prognostic indicators than PAP.23-25
Changes in peak PAP alone can be difficult to use for assessing disease progression without knowing
the change in cardiac output. In fact, in one study, a fall in PAP correlated negatively with survival.26
RAP and RV end-diastolic pressure typically rise before RV systolic function deteriorates and have
been shown to be better predictors of mortality than PAP alone. RAP greater than 15 mm Hg is
associated with a nearly 2-fold greater mortality.27 A rise in RAP may result from worsening tricuspid
insufficiency or from elevation of RV end-diastolic pressure.
The importance of RV function in PAH cannot be overemphasized. Most patients tolerate an elevated
PVR fairly well, provided that they have a pump that is strong enough to maintain adequate flow
through the lungs. A rise in RV end-diastolic pressure generally means that RV systolic function is
unable to compensate for the sustained elevation in afterload, and the right ventricle is attempting
to compensate by increasing preload.
The normal right ventricle can maintain systolic function as filling pressure increases, but increases
in afterload are not as well tolerated as they are in the left ventricle (Figure 3). At a certain point,
further increases in RV afterload result in decreased stroke volume and cardiac failure. An increase
in RV end-diastolic pressure, usually above 10 mm Hg in a patient with PAH, is concerning and
warrants consideration of additional therapy to lower PVR even if the patient's other hemodynamic
and clinical parameters are unchanged.
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Figure 3 – These are the effects of right and left ventricular filling pressures and afterload on stroke
volume in dogs. Stroke volume is better maintained by the right ventricle (RV) than by the left
ventricle (LV) as filling pressure increases (A), but systolic function deteriorates rapidly as right
ventricular afterload is increased by constriction of the pulmonary artery (B). (Reproduced with
permission from Braunwald E et al, eds. Braunwald’s Heart Disease: A Textbook of Cardiovascular
Medicine. 2004.29)
Unfortunately, pulmonary artery catheterization is an expensive and invasive procedure that is not
without risk of serious complications and can expose the patient to high levels of radiation. These
limitations frequently dampen the enthusiasm that many practitioners have for the technique, so it
often is the diagnostic test of last resort. This is unfortunate, because by the time the patient's
condition has worsened, pulmonary artery catheterization is more likely to confirm clinical findings
than to supply new information that may have helped prevent or slow disease progression. In many
pulmonary hypertension centers, right heart catheterization is often repeated routinely after the first
6 to 12 months of therapy, even in patients whose conditions have not deteriorated, to ensure that
findings from less invasive monitoring techniques are accurate.
References:
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