| Harold L Dauerman, MD James P Morgan, MD, PhD |
May 10, 1998 |
Secondary pulmonary artery hypertension (SPAH) refers to an increase in pulmonary artery impedance due to either intrinsic parenchymal lung disease or disease extrinsic to the lung. (Patients without an identifiable cause have primary pulmonary hypertension.) Pulmonary hypertension is considered to be present when pulmonary artery systolic and mean pressures exceed 30 mmHg and 20 mmHg, respectively.
This card will review the clinical manifestations and diagnosis of SPAH. The major causes of this disorder, which are discussed separately, include chronic obstructive lung disease (COPD), mitral valve disease (particularly mitral stenosis), collagen vascular diseases, and atrial or ventricular septal defects. (See "Causes of secondary pulmonary hypertension").
CLINICAL MANIFESTATIONS ！ The clinical manifestations of SPAH are frequently masked by the underlying etiology, and the diagnosis is confirmed only after the onset of right ventricular failure. This is a relatively common problem. Cor pulmonale (right ventricular failure secondary to intrinsic respiratory disease) is the third most frequent cause of cardiac dysfunction, after coronary and hypertensive heart disease, in patients over the age of 50 [1].
The development of PAH and right ventricular dysfunction often has important prognostic implications. Patients with COPD, for example, have a three year mortality of 60 percent after the onset of right ventricular hypertrophy [2].
Symptoms ！ Patients with SPAH often have nonspecific symptoms which reflect the underlying etiology. There are, however, symptoms directly attributable to SPAH including dyspnea on exertion, fatigue, lethargy, chest pain, and syncope with exertion.
• Fatigue, lethargy and exertional syncope reflect an inability to increase cardiac output during stress because of vascular obstruction in the pulmonary arterioles .
• Typical exertional angina has been reported in up to 8.5 percent of patients with mitral stenosis and PAH, despite having normal coronary arteries [3]. The mechanism by which angina occurs is unclear, as both pulmonary artery stretching and right ventricular ischemia have been proposed. The importance of right ventricular ischemia induced by hypoxemia during exertion was suggested in a case report in which angina was associated with electrocardiographic changes of right ventricular strain and was relieved with long-term oxygen therapy [4]. (See "Guidelines for long-term supplemental oxygen therapy"). Oxygen administration was also associated with the development of right ventricular hypertrophy (RVH), indicating the compensatory role of hypertrophy in this setting.
Less common symptoms directly related to PAH include cough, hemoptysis and hoarseness (due to compression of the left recurrent laryngeal nerve by a dilated main pulmonary artery).
Different symptoms may predominate at a later stage when there has been progression to right ventricular failure. In this setting, passive hepatic congestion can lead to complaints such as anorexia and right upper quadrant discomfort.
Physical findings ！ The physical examination should detect findings characteristic of pulmonary hypertension and right ventricular hypertrophy; signs of right ventricular failure also may be present in more advanced disease.
• The initial physical finding of PAH is increased intensity of the pulmonic component of the second heart sound, which may even become palpable. The second heart sound may also be narrowly split, a change that will not be present if right ventricular depolarization is delayed because of concurrent right bundle branch block. Auscultation of the heart also may reveal a systolic ejection murmur and, in more severe disease, a diastolic pulmonary regurgitation murmur. (See "Auscultation of cardiac murmurs-I" and see "Auscultation of heart sounds-I").
• Right ventricular hypertrophy is characterized by a prominent A wave in the jugular venous pulse, associated with a right sided fourth heart sound, and either a left parasternal heave or a downward subxiphoid thrust. (See "Examination of the precordial pulsation").
• Right ventricular failure leads to systemic venous hypertension. This can lead to a variety of findings such as elevated jugular venous pressure with a prominent V wave, a right ventricular third heart sound, and a high pitched tricuspid regurgitant murmur. (See "Examination of the jugular venous pulse"). Extracardiac changes that may be seen include hepatomegaly, a pulsatile liver (if tricuspid regurgitation is prominent), and peripheral edema. Ascites is uncommon, even in severe cor pulmonale [5].
The right sided murmurs and gallops are augmented with inspiration, but these findings may be obscured, depending upon the etiology of the PAH. In severe emphysema, for example, the increased anteroposterior diameter of the chest makes auscultation difficult and changes the position of the right ventricular impulse. (See "Examination of the precordial pulsation").
Edema ！ Some patients with severe COPD develop edema in association with clear evidence of right heart failure (associated with worsening hypoxemia and hypercapnia and possibly mediated in part by hypoxemic pulmonary vasoconstriction); others, however, have no hemodynamic signs of right ventricular failure and pulmonary artery pressure and arterial blood gases are stable [6]. The pathogenesis of edema in such patients is not well understood: the cardiac output and glomerular filtration rate are usually normal or near normal both in the resting state and with exercise [7,8]. Edema may form in these patients due to hypercapnia or hypoxemia:
Edema seems to occur primarily in patients with hypercapnia, suggesting that the high PCO2 rather than cardiac dysfunction may be responsible for the sodium retention in cor pulmonale [9]. Hypercapnia is associated with an appropriate increase in proximal bicarbonate reabsorption, which serves to minimize the fall in arterial pH. This increase in proximal bicarbonate transport contribute edema formation in cor pulmonale, since it also promotes the passive reabsorption of sodium chloride and water [10]. (See "Chapter 3A: Cell model for proximal transport-I").
Another contributing factor to sodium retention may be hypoxemia. Hypoxemia can cause renal vasoconstriction, leading to a reduction in urinary sodium excretion [11].
DIAGNOSIS ！ The history and clinical features may suggest a particular cause for SPAH but confirmation of the diagnosis usually requires performance of one or more procedures. Right heart catheterization is the gold standard; however, it is often possible to establish the diagnosis with noninvasive methods, with catheterization being used in selected patients if additional information is required
Chest radiograph ！ The characteristic chest x-ray in PAH shows enlargement of the central pulmonary arteries (show radiograph 1A-1B).
In addition, the peripheral vessels are attenuated, leading to oligemic
lung fields. Right ventricular and right atrial dilatation are later findings
that are seen as the disease progresses to right ventricular failure. Right
ventricular enlargement can also lead to a decrease in the retrosternal space.
However, these findings may be obscured in the presence of kyphoscoliosis,
hyperinflated lungs, left ventricular enlargement, or interstitial lung
disease.
Electrocardiogram ！ The electrocardiogram
may demonstrate signs of right ventricular hypertrophy or strain (show
ECG 1).
In acute pulmonary embolism, for example, a classic pattern of an S wave
in lead I with a Q and inverted T wave in lead III may be seen. Findings that
may be seen in chronic right ventricular overload include:
• Right axis deviation and R/S ratio greater than
1 in lead V1.
• Increased P wave amplitude in lead II (P
pulmonale) due to right atrial enlargement (show
figure 2
and show
ECG 2).
• Incomplete or complete right bundle branch
block.
Most electrocardiographic criteria show a high specificity (ie, the findings
are absent in patients without the disease) but a low sensitivity (ie, the
findings are present in patients with the disease) for the detection of RVH.
The sensitivity of the electrocardiogram is even worse in patients with
biventricular hypertrophy or COPD [12].
Two dimensional echocardiography ！ Most
patients with PAH have two dimensional echocardiographic signs of chronic
right ventricular pressure overload (show
echocardiogram 1,
show
echocardiogram 2,
and show
echocardiogram 3).
The elevation in pressure leads to increased thickness of the right
ventricle with paradoxical bulging of the septum into the left ventricle
during systole (show
figure 3).
At a later stage, right ventricular dilatation occurs and the septum
shows abnormal diastolic flattening.
Stress on the right heart initially produces hyperkinesis. However, this is
eventually followed by right ventricular hypokinesis, associated with right
atrial dilatation and tricuspid regurgitation. The latter is not due to an
intrinsic abnormality of the tricuspid valve; it is a secondary manifestation
of dilatation of the tricuspid annulus and right ventricle [13].
Doppler echocardiography ！ Doppler
echocardiography is the most reliable noninvasive estimation of the pulmonary
artery pressure. This technique takes advantage of the functional tricuspid
insufficiency usually present in PAH. The maximum tricuspid regurgitant jet
velocity is recorded and the pulmonary artery pressure (PAP) is then
calculated by the modified Bernoulli equation:
where RAP is the right atrial pressure estimated from the size and respiratory
variation of flow in the inferior vena cava. Other findings
associated with pulmonary hypertension are pulmonic insufficiency and
midsystolic closure of the pulmonic valve [14,15].
(See
"Principles of Doppler echocardiography").
The efficacy of Doppler echocardiography may be limited by the ability to
identify an adequate tricuspid regurgitant jet. It may also be less sensitive
because of alterations induced by the underlying disease. For example,
acoustic windows in patients with COPD may be limited by the increased
anteroposterior diameter of the chest.
Despite these potential problems, Doppler estimation using tricuspid
regurgitation is far more sensitive than the clinical examination and can make
an accurate diagnosis in the majority of patients. This is illustrated by the
following observations:
• In one report, Doppler ultrasound examination
was able to identify tricuspid regurgitation in 80 percent of 69 patients with
catheterization-documented PAH (PA systolic pressure above 35 mmHg) [16].
The accuracy was even higher in patients with more severe disease (PA systolic
pressure above 50 mmHg). Tricuspid regurgitation was detected in 95 percent of
these patients and there was a 97 percent correlation with the pressure
measured by catheterization.
• Another study of 33 patients with severe COPD
compared clinical and echocardiographic criteria in establishing the diagnosis
of PAH [17].
Echocardiographic cor pulmonale was said to be present when the right
ventricular free wall thickness was >0.6 cm in the subxiphoid view, PA
systolic pressure was greater than 40 mmHg by tricuspid jet Doppler with
saline contrast, and the RV/LV ratio was increased. Clinical criteria included
right ventricular hypertrophy on the electrocardiogram, enlarged pulmonary
arteries on the chest x-ray, and physical findings such as a loud pulmonic
heart sound, parasternal heave, jugular venous distension, edema, and
hepatomegaly. Cor pulmonale was identified by clinical criteria in only 39
percent of patients versus 75 percent with echocardiography. The use of saline
contrast significantly enhanced the sensitivity of Doppler ultrasound in
detecting tricuspid regurgitation.
Exercise echocardiography ！ There is a
group of patients with exertional symptoms in whom PAH can only be diagnosed
with exercise. In this setting, exercise echocardiography is the noninvasive
technique of choice. In one study of 36 patients with a variety of chronic
lung diseases, for example, 28 percent of those with normal resting PA
pressures had significant PAH after bicycle ergometry using saline enhanced
contrast echocardiography [18].
In 10 patients, simultaneous right heart catheterization showed a 98 percent
correlation between exercise Doppler and catheterization estimates of
pulmonary artery systolic pressure.
Pulmonary function tests ！ Pulmonary
function tests should be performed in patients with a suggestive history of
underlying lung disease and in those with normal cardiac function. An
obstructive pattern is suggestive of COPD. These tests can also aid in the
diagnosis of interstitial lung disease. It is important to appreciate that
only severe interstitial lung disease (with lung volume below 50 percent of
normal) produces SPAH, while a mild restrictive defect can be produced by PAH
itself. Thus, the latter finding is not indicative of interstitial lung
disease as a cause of SPAH.
Right-sided cardiac catheterization ！
Catheterization of the right heart is the gold standard for the diagnosis,
quantification, and characterization of PAH (show
radiograph 2).
This procedure is indicated only when the necessary information cannot
be obtained with Doppler echocardiography. Current indications include:
• When echocardiography does not permit
measurement of a tricuspid regurgitant jet, which does not exclude significant
pulmonary artery hypertension [15].
• When symptoms are exertional and simultaneous
measurement of left-sided pressures during exercise are indicated.
• When therapy will be determined by precise
measurement of pulmonary vascular resistance and the response to vasodilators.
• For verification of the presence and severity
of congenital and acquired left-to-right shunts, if the measurements are
unclear from prior testing.
• When left heart catheterization is required as,
for example, in the patient over 40 years of age or with risk factors for
coronary disease who is a candidate for surgical repair of a shunt. In this
setting, preoperative evaluation of the coronary arteries may be desirable.
Right heart catheterization can also be used to determine the potential
reversibility of PAH using vasodilators such as nitroprusside,
prostacyclin, or nitric oxide [19,20].
This information can be used to predict whether repair of a left-to-right
shunt will be beneficial or, in a prospective cardiac transplant recipient,
whether heart-lung transplantation is required. (See appropriate cards).
Lung biopsy ！ Pathological assessment of
pulmonary artery hypertension requires lung biopsy. Historically, pathological
examination has been used intraoperatively to look for evidence of
irreversible pulmonary artery pathology. At present, right heart
catheterization assessment of pulmonary vascular resistance and the
vasodilator response are usually adequate to guide therapeutic decisions [21].
Other studies ！ Intravascular ultrasound
may provide similar information without a lung biopsy. In a small study of
patients with PAH from a variety of causes, autopsy comparison of histologic
examination and intravascular ultrasound (IVUS) assessment of wall thickness
and pathology showed a significant correlation between the two methods [22].
However, a direct in vivo comparison to lung biopsy has not yet been
performed.
Brain natriuretic peptide (BNP) is similar in its structure and activities to
atrial natriuretic peptide but is produced primarily in the cardiac ventricles
and therefore may be more sensitive and specific for the early detection of
right ventricular dysfunction due to pulmonary hypertension. (See
"Natriuretic hormones: Atrial peptides and ouabain-like hormone").
One study of 44 patients with right ventricular volume overload due to atrial
septal defects or right ventricular pressure overload due to primary pulmonary
hypertension or chronic thromboembolic disease found that plasma BNP
concentrations correlated positively with mean pulmonary artery pressure,
total pulmonary resistance, and right ventricular mass [23].
Patients with right ventricular pressure overload had significantly higher
plasma BNP levels than patients with right ventricular volume overload,
suggesting that BNP measurements may assist in determining the etiology of
pulmonary hypertension.
RECOMMENDATIONS ！ The history, physical
examination, chest radiograph, and electrocardiogram may suggest the presence
of PAH and right ventricular dysfunction, although the expected findings are
frequently obscured by the underlying etiology.
• Two-dimensional transthoracic echocardiography
with Doppler analysis can be used to confirm the diagnosis of PAH and to
exclude possible cardiac disease. In most patients, the presence of PAH can be
established by analysis of the tricuspid regurgitant jet. The addition of
saline contrast and exercise increases the sensitivity of this test.
• In patients without primary cardiac disease,
pulmonary function tests should be obtained, including blood gases and
assessment of possible nocturnal desaturation. The findings can point toward
COPD or interstitial lung disease, which can be evaluated further with CT scan
and possible lung biopsy.
• Patients with relatively normal pulmonary
function tests should undergo a perfusion lung scan and, if defects are
present, pulmonary angiography.
• We recommend right heart catheterization if the
presence of PAH is strongly suspected but noninvasive testing is not
definitive. Right heart catheterization also permits assessment of the
reversibility of pulmonary artery hypertension with vasodilators, and
quantification of pulmonary vascular resistance. This information can be used
to estimate the likelihood of success of potential medical and/or surgical
intervention.