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Pulmonary Hypertension

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					                     PULMONARY HYPERTENSION
Jigme Sethi, M.D.

LEARNING OBJECTIVES

1. To be able to list the causes of pulmonary hypertension based on the
   underlying mechanism
2. To understand the changes in cardiac function produced by chronic
   pulmonary hypertension

THE PULMONARY CIRCULATION IN HEALTH

The pulmonary circulation is a low-resistance, low-impedance, highly
compliant and therefore high-capacitance vascular bed. It is highly dependent
upon the performance of the two ventricles it connects, and because the
capillaries of the pulmonary circulation run within the walls of the alveoli, the
resistance of the pulmonary vasculature depends upon airway (and pleural)
pressures. It is poorly equipped for self-regulation, unlike the coronary or
cerebral circulation. At any time, a given stroke volume ejected from the RV is
proportioned into a pass-through component that returns to the LV, and a stored
component that remains temporarily within the pulmonary vasculature. The
capacitance of the pulmonary circulation is approximately 400-500 ml, or about a
tenth of the circulating blood volume. The pulmonary capillary blood volume is
about 100-200 ml, and circulation time is about 0.75 sec.

The blood flow through the lungs is equal to the alveolar ventilation, and both
occur in a phasic manner, but the rates are different (respiratory rate is much
slower than heart rate). Therefore matching of blood flow to ventilation occurs on
a regional basis by means of a system of hypoxic vasoconstriction, in that
vessels in poorly ventilated, hypoxic areas of the lung are vasoconstricted so as
not to waste blood flow to those poorly gas exchanging areas. This is
fundamentally different from the systemic circulation where arterioles dilate
in areas of hypoxemia and poor oxygenation.

Pulmonary vascular resistance is defined by the equation: R= Ppa-Pla/ Q, where
Ppa-Pla is the difference of mean pressures between the pulmonary artery and
the left atrium respectively, and Q is the pulmonary blood flow in L/min. Normal R
is 0.1mmHg/L/min (or 100 dynes/sec.cm5)

Changes in PVR can be either active or passive. Active changes refer to
changes in arterial tone mediated by the sympathetic nerves or hypoxic
vasoconstriction (see below), whereas passive changes are alterations of caliber
or pressure resulting from changes in lung volumes, gravitational effects and
recruitment.
Changes in the structure of the pulmonary vessels, or so-called remodeling, can
also change PVR, and therefore, the pressure in the circulation. For example, the
fetal vessels are thicker and more muscularized than adults and failure of this
muscularization to regress in the neonatal period causes persistent pulmonary
hypertension. Similarly, unlike the yak, which is native to high altitudes, humans
living at high altitude have muscularized vessels and therefore higher PVR, and
higher pulmonary arterial pressures for a given cardiac output. Thus at 4540m
with an ambient P02 of 80 mmHg, the mean PA pressure is about 28 mmHg in
healthy humans, twice that of persons at sea level (about 12 mmHg), with the
same cardiac output.

THE DEFINITION OF PULMONARY HYPERTENSION

Pulmonary hypertension is defined as sustained elevations of pulmonary mean
arterial pressures more than 25 mmHg at rest or 30 mmHg on exercise.
Ordinarily, mean pulmonary artery pressures are around 10-12 mmHg in health.
Aging is associated with a slight increase in mean pressures but less than the
diagnostic criteria for the definition. These criteria apply to persons living at sea
level.

Pulmonary hypertension without a known underlying cause is termed primary
pulmonary hypertension, and is a unique disorder affecting young women
predominantly, with an incidence of approximately 1-2/million in the general
population. Familial forms of the disease constitute about 6% of PPH cases, and
are autosomal dominant with genetic anticipation. The majority of PPH patients
have the clinically identical sporadic form.

Secondary pulmonary hypertension occurs when an underlying cause can be
demonstrated (see below). Although the manifestations of the pulmonary
hypertension are mostly similar to the PPH variety, the underlying cause usually
overshadows the more subtle abnormalities attributable to the pulmonary
hypertension. Thus the manifestations of emphysema are prominent long before
the symptoms of secondary pulmonary hypertension appear in the patient.

Cor pulmonale exists when the right ventricle dilates and fails from exposure to
high pulmonary artery pressures.

PATHOPHYSIOLOGICAL TYPES OF PULMONARY HYPERTENSION

The processes that give rise to pulmonary hypertension are a combination of
increased vasoconstriction of the pulmonary arteries, structural changes that
result in increased vascular resistance (remodeling), and various degrees of
intra-vascular thrombosis causing further obstruction to pulmonary blood flow.
1. Passive Pulmonary Hypertension: Elevated left heart filling pressures
   (usually a PAWP above 20 mmHg) lead passively to pulmonary venous
   hypertension, followed thereafter by reactive vasoconstriction, and
   structural remodeling of the pulmonary arterial and venous beds, resulting
   in further pulmonary hypertension. Reactive vasoconstriction of the small
   pulmonary arteries can be attenuated, in experimental models, by alpha
   adrenergic blockers such as phentolamine or calcium channel blockers
   such as nifedipine. Dilatation and medial hypertrophy of the pulmonary
   veins, and eccentric intimal fibrosis of the arteries and veins are seen as a
   result of remodeling. Both the vasoconstriction and the remodeling reverse
   rapidly after alleviation of the downstream elevations in LV filling
   pressures (e.g. surgical correction of mitral stenosis) with reversal of
   pulmonary hypertension.
2. Hyperkinetic Pulmonary Hypertension: This entity is seen in conditions
   causing high flow through the pulmonary circulation in combination with
   pressure overload. Normal humans can increase blood flow through the
   pulmonary circulation by a factor of 4 without appreciably changing PA
   pressure, due to a combination of recruitment of hitherto collapsed vessels
   and vasodilatation leading to a lower PVR under such circumstances.
   However, in the presence of a high flow Left to Right Shunt, as in a VSD
   or PDA, the pulmonary circulation is exposed to a combination of pressure
   overload generated by the left ventricle and the increased flow, leading to
   reactive vasoconstriction and then remodeling. In the case of a shunt at
   the atrial level, usually the elevations of PA pressure are modest and
   reflect the absence of exposure to LV pressures. Additionally, in the
   neonate, the elevated flows and pressures resulting from a shunt from left
   to right, are superimposed upon the failure of involution of the thick arterial
   media, aggravating the pulmonary hypertension. The structural
   remodeling in hyperkinetic pulmonary hypertension is reversible if the
   changes are limited to medial hypertrophy, extension of muscular coats
   into non-muscular distal pulmonary arteries and intimal fibrosis, but
   become irreversible if plexiform lesions are present. Reversal of the
   direction of shunting to right to left due to the very high PA pressures is
   called Eisenmenger’s syndrome.
3. Obstructive Pulmonary Hypertension: This may be seen in situations
   where the pulmonary bed is obstructed by chronic thromboembolic
   disease, or in schistosomiasis where parasite eggs are deposited in the
   pulmonary vessels. Over time, remodeling takes place, and the
   obstructions become fixed, leading to pulmonary hypertension. Chronic
   thromboembolic disease must always be excluded in unexplained cases
   of pulmonary hypertension.
4. Obliterative Pulmonary Hypertension: This results from loss of the
   pulmonary vascular bed as a whole due, for example, to emphysema
   where alveolar surface area is lost from destruction of the walls of the
   alveoli, along with their component capillaries. Similar destruction of the
     pulmonary vasculature is seen in the extensive destruction resulting from
     pulmonary fibrosis.
  5. Vasoconstrictive Pulmonary Hypertension: Unlike the systemic arteries
     which vasodilate in response to hypoxia or hypoxemia, the pulmonary
     arteries react by vasoconstriction. Thus, diseases of the lungs resulting in
     chronic hypoxia, e.g. severe COPD, pulmonary fibrosis, long-standing
     obstructive sleep apnea, or end stage sarcoidosis, or extensive right to left
     shunting through the myriad arteriovenous spiders of hereditary
     hemorrhagic telengiectasia can lead to vasoconstriction as the primary
     pathophysiological basis for the pulmonary hypertension that ensues.

     In other situations, the vasoconstriction can be idiopathic, or of unknown
     cause. Although Primary Pulmonary Hypertension or PPH is the classic
     example, other associations include HIV disease, anorexigen use, inhaled
     cocaine abuse, connective tissue disorders (SLE, RA, scleroderma, or
     mixed connective tissue disease) and liver disease (so-called
     portopulmonary hypertension)..

     This classification, though somewhat simplistic in pathophysiological
     terms, is extremely useful clinically, and the approach to establishing the
     etiology of the pulmonary hypertension in a given patient must proceed
     along the orderly schema outlined above. Thus, primary pulmonary
     hypertension is excluded if left ventricular failure exists with elevated
     pulmonary capillary wedge pressures, if an un-repaired VSD can be
     detected on echocardiogram, or if extensive pulmonary fibrosis or chronic
     thromboembolism can be established.

PATHOLOGY OF PULMONARY HYPERTENSION

  1. The earliest pathological change in pulmonary hypertension of any
     etiology is that of medial hypertrophy with thickening of the muscular
     media of pulmonary arteries and extension of muscular media into
     previously non-muscularized pulmonary vessels. While smooth muscle
     stretch and elevated pressures can stimulate proliferation of smooth
     muscle cells, elevated endothelin-1 levels can mediate smooth muscle
     proliferation.
  2. While intimal proliferation leading to intimal fibrosis and concentric
     intimal hyperplasia is a later feature of pulmonary hypertension, two
     aspects of endothelial dysfunction bear special mention. First, endothelial
     dysfunction of a more subtle nature may well underlie the development of
     pulmonary hypertension. Thus loss of endogenous endothelial derived
     relaxing factor, or NO, may predispose to vasoconstriction, as may
     overproduction of the potent vasoconstrictor substance endothelin-1.
     Similarly, increases in the endothelial content of von willebrands factor as
     is seen in PPH or patients with high flow left to right shunts, may
     predispose to local thrombosis. Second, the hallmark lesion of pulmonary
      arterial hypertension, especially, (but not limited to) PPH, is the plexiform
      lesion, a complex branching system of endothelial channels within the
      lumen of the pulmonary arteries. This must be differentiated from
      recanalized thrombi obstructing the pulmonary vessels. In familial PPH,
      the endothelial cells forming the plexiform lesions are monoclonal in
      origin, and indeed the gene for familial hypertension has been localized to
      a short segment of chromosome, but remains to be exactly characterized.
   3. Thrombosis occurring in situ is another characteristic abnormality in the
      smaller vessels of the hypertensive pulmonary circulation, and must be
      distinguished from the larger obstructing clots in the proximal vessels that
      characterize thromboembolic pulmonary hypertension.

CONSEQUENCES OF CHRONICALLY HIGH PULMONARY ARTERY
PRESSURES

The right ventricle bears the brunt of the hemodynamic burden imposed by
chronically elevated PA pressures. Although normally a thin walled chamber with
a crescent-shaped cavity on cross section, after exposure to high PA pressures
for a prolonged period, it dilates, initially developing a more ovoid cross sectional
chamber pattern. Progressive thickening of the wall ensues and it can finally
exceed LV thickness in the most advanced cases. In severe pulmonary
hypertension, the combination of free wall thickening and dilatation imposed by
incomplete emptying against high PA pressures leads to bowing of the septal
wall into the LV cavity, encroaching upon LV size, filling, and therefore, stroke
volume.

These changes in the structure of the right ventricle are adaptive in nature—
designed to preserve RV output in the face of increased pulmonary artery
pressures and hence, afterload. The adaptive nature of the response can be best
understood by reviewing the cardiac response to exercise as pulmonary
hypertension progresses. The normal response to exercise consists of an
increase in cardiac output, a consequent “hyperkinetic” increase in pulmonary
artery pressure that is however blunted by recruitment and distension of
pulmonary vasculature, and no change in pulmonary wedge pressure. All of this
is accomplished without an increase in RV end-diastolic pressure, which is a
negative marker of RV compliance and ejection efficiency. As pulmonary
hypertension develops, baseline PA pressures and exercise-induced increments
increase, but RV hypertrophy and dilatation allow appropriate increases in
cardiac output, albeit at the cost of an increasing RVEDP. In the stage of RV
failure however, the extremely high PA pressure overcomes the compensatory
RV remodeling and cardiac output fails to rise appropriately with exercise.

Since RV adaptation maintains CO in the face of high PA pressures, it follows
that RV function may be a predictor of survival in patients with pulmonary
hypertension. Genetic factors may also predict which patients will adapt
appropriately in terms of RV remodeling, and hence determine outcome. In
general, once RV failure develops, patients usually die in <1 year, in contrast to a
3.5-5.0 year survival in patients with preserved RV function.

PRIMARY PULMONARY HYPERTENSION: SALIENT FEATURES

This is a rare disease, with an incidence of 1-2 per million, affecting
predominantly young to middle aged women. 6% of the incidence of PPH is
accounted for on a familial, autosomal dominant basis. One important gene,
PPH1, encoding for Bone Morphogenetic Protein Receptor Type II (BMPR II) has
been identified, and there is growing evidence that dysfunction of the receptor
leads to abnormal proliferation of vascular endothelial cells, such as is seen in
the plexiform lesion. Subjects with the haplotype have elevated PA pressures
during exercise even while they have normal PA pressures at rest—a potential
screening test.
The exact mechanism of the disease is not known. There is clearly an imbalance
of vasodilator and vasocontrictor substances in the regional pulmonary
circulation. Reduced expression of nitric oxide synthase and prostacyclin
synthase in the pulmonary endothelium leads to decreased activity of nitric oxide
and prostacyclin, both very potent vasodilators. On the other hand, endothelin, a
potent vasoconstrictor and endothelial cell mitogen, is overexpressed in the lungs
of PPH patients, and elevated plasma levels are correlated with disease severity
and worsening prognosis.

CLINICAL FEATURES OF PULMONARY HYPERTENSION

The primary symptom experienced by patients with isolated primary pulmonary
hypertension is dyspnea, and this is the chief complaint in up to 60% of patients.
As the PA pressures rise with a resulting drop in RV ejection fraction leading to a
reduction in cardiac output, fatigue and reduced exercise tolerance become
more prominent symptoms. Since the cardiac output is fixed and reduced by the
elevated PA pressures and does not rise appropriately with increased needs,
these symptoms are initially pronounced during exercise. In addition, during
exercise, due to systemic vasodilatation, blood pressure may fall and if the
cardiac output cannot rise appropriately, patients may experience syncope or
sudden death. Hemoptysis is a relatively uncommon symptom and is often due
to bleeding from unrelated causes, such as bronchitis or endobronchial lesions.
It may, however, also be precipitated by the high pulmonary artery pressures.
10% of patients with PPH, usually women, report Raynaud’s phenomenon.
Other clues to the diagnosis can be categorized as follows:

Evidence of elevated pulmonary arterial pressures: ejection systolic murmur
over the pulmonic area, often with wide splitting of the S2 (i.e. delayed P2
component). P2 may be accentuated enough to be louder than A2, and may
even be heard in the mitral area.
Evidence of right ventricular pressure overload: Parasternal heave, raised
JVP, often with the elevated CV waves of triscuspid regurgitation, and later in the
course of the disease, hepatomegaly with nutmeg liver and congestive
hepatopathy, and leg edema. Ascites and pleural effusions may also be seen in
advanced pulmonary hypertension.

Evidence of loss of the pulmonary vascular bed: elevated A-a gradient,
hypoxemia, cyanosis, and decreased diffusion capacity for Carbon Monoxide.
Other pulmonary function tests will reflect the underlying etiology for the
pulmonary hypertension, e.g. severe obstruction in cor pulmonale from
emphysema, or severe restriction in pulmonary fibrosis, or an increased shunt
fraction in patients with Hereditary Hemorrhagic Telengiectasias.

Evidence of reduced cardiac output: In the later stages, as right ventricular
ejection fraction drops due to the high afterload of the right ventricle, cardiac
output falls, and patients complain of severe fatigue in addition to shortness of
breath, and may be orthostatic. The same situation can be seen if patients with
pulmonary hypertension are over-diuresed in an effort to reduce the leg edema
resulting from RV failure. Cardiac output drops, patients may be dizzy or
orthostatic or syncopal, and complain more of fatigue than dyspnea.

Evidence of pulmonary hypertension on the chest radiograph includes dilated
pulmonary arteries (main right descending pulmonary artery width greater than
1.4 cm in a female or more than 1.6 cm in a male), dilated pulmonary outflow
tract bulging out beyond the aortic knuckle on the left side of the cardiac
silhouette, pruning of pulmonary vasculature (vessels cannot be traced out to
within 2 cm of the edge of the lung as is normal), and dilatation of the RV with
uplifting of the apex of the heart from the left hemidiaphragm. On the EKG, right
ventricular hypertrophy is suggested by right axis deviation or a right bundle
branch block pattern. On echocardiography, if tricuspid regurgitation is present,
as it often is, the systolic PA pressures can be estimated by adding 4 x the
square of the regurgitation jet velocity, to the CVP. The right ventricle may be
hypertrophic or dilated, and occasionally clots can be seen in the proximal
pulmonary arteries in patients with thromboembolic pulmonary hypertension. A
VSD may be seen if that is the cause of the hypertension. 25% of normal adults
have a patent foramen ovale, through which right to left shunting may take place
if PA pressures are very high, further exacerbating the hypoxemia. Therefore, a
bubble study should always be obtained—either direct shunt through the patent
foramen ovale may be detected, or hypoxic pulmonary hypertension diagnosed if
premature appearance of bubbles in the left side of the heart within 6 cycles
suggests a right to left shunt through an unsuspected AV malformation in the
lung or elsewhere. A V/Q scan should not be abnormal in pulmonary
hypertension unless there is underlying chronic thromboembolic disease, or other
parenchymal lung disease causing pulmonary hypertension. A spiral CT scan of
the chest with radio-opaque contrast may well show the clots obstructing the
lumen of the pulmonary arteries in those with thromboembolic disease, but a
pulmonary angiogram which outlines only the lumen of the arteries may well miss
these clots. Nevertheless the angiogram is very useful in detecting pulmonary
artery malformations or macroscopic telengiectasias that may cause shunting
with hypoxemia and ensuing hypoxic pulmonary hypertension, and sometimes in
detecting pulmonary thromboembolic disease. It is not often required however. A
right heart catheterization is diagnostic, allowing measurement of PA systolic,
diastolic and mean pressures, calculation of pulmonary vascular resistance,
determination of cardiac output, measurement of elevated left heart filling
pressures (i.e., the PAWP) and occasionally, detection of step-ups in oxygen
saturation in the right atrium or right ventricle resulting from left to right shunts at
those levels. Finally, right heart catheterization allows observations of responses
to some therapeutic interventions such as infusion of prostacyclin, inhaled nitric
oxide, or orally-acting calcium channel blockers.

The etiology of the pulmonary hypertension should suggest itself on the history or
physical, by providing clues to the presence of the various diseases listed as
causes in the various categories. If no obvious clinical cause is apparent, then
serology for connective tissue disorders, testing for HIV or liver disease,
especially cirrhosis, search for thromboembolic disease and procoagulant
disorders, a sleep study to rule out sleep apnea, a history to exclude anorexigen
or cocaine use or travel to areas endemic for schistosomiasis, and an
echocardiogram to detect occult valvular disease such as mitral stenosis, mitral
valve prolapse or diastolic disease, are appropriate. A high resolution CT scan
may be used to screen for occult pulmonary parenchymal disorders where the
chest x-ray is normal, as occurs in a proportion of patients with pulmonary
fibrosis, or bronchiectasis for example. An arterial blood gas may show evidence
of unsuspected alveolar hypoventilation, as in patients with obesity
hypoventilation or Pickwickian syndrome, and unexplained hypoxemia should
suggest a shunt if supplemental oxygen does not improve the hypoxemia.
Finally, the diagnosis of PPH is one of exclusion, in all circumstances.

It is important to note however, that the clinical stigmata of pulmonary
hypertension, may be very subtle in the early stages of the disease, especially in
young patients with the primary form, and one must not wait for evidence of right
ventricular failure to develop before investigating for the disease. Every patient
with dyspnea and hypoxemia or cyanosis, developing over months, with a
clear chest X-ray and no evidence of cardiac abnormalities, especially if
young, should be investigated for this disease. The mean length of time to
diagnosis is about 2 years in 90% of patients with PPH.

MANAGEMENT OF PULMONARY HYPERTENSION

   1. Treat the underlying cause: For example, this could involve treating the
      left sided heart failure, resorting to a mitral valve commissurotomy for
      mitral stenosis, surgical correction of a shunt, treatment of sleep apnea,
      discontinuing any anorexigen use, optimal treatment of COPD, etc.
2. In particular, emphasis should be placed on correcting hypoxia, which
   predisposes to accelerated pulmonary hypertension in patients with
   COPD, sleep apnea, or advanced lung disease. Oxygen is an excellent
   pulmonary vasodilator! Screen for hypoxemia during exertion, and
   provide supplemental oxygen during exertion. Care must be taken to
   detect and eliminate occult nocturnal desaturations, which over time can
   exacerbate pulmonary hypertension. Look for and close if possible, any
   major shunting through a patent foramen ovale for example, and
   especially suspect a shunt if patients do not respond to supplemental
   oxygen with improved saturations or exercise tolerance.
3. Anticoagulate patients with advanced pulmonary hypertension: This has
   been shown to improve survival in a few studies, and since thrombosis is
   such a common finding in all forms of advanced pulmonary hypertension,
   it has a sound basis. Anticoagulation reduces in situ thrombosis, and the
   incidence of thromboembolism in patients predisposed to DVT due to leg
   edema and heart failure.
4. Warn against vigorous exertion—exercise may precipitate an acute drop
   in blood pressure, syncope, and even death.
5. Diurese gently, since in right ventricular failure, the pressure overloaded
   right ventricle may cause the septum to bulge into the left ventricle raising
   LVEDP and cause pulmonary edema. Diurese cautiously, since the RV
   relies on elevated preload to maintain ejection in the face of elevated
   afterload, so that overdiuresis can lead to a further, deleterious, and
   avoidable reduction in cardiac output. Digoxin has limited use, perhaps
   only in patients on the negatively inotropic calcium channel blockers.
6. Vasodilator therapy is useful in selected patients, i.e. those with PPH
   and pulmonary hypertension resulting from Scleroderma and perhaps
   other connective tissue diseases, or HIV. However there is increasing
   data that some of these agents are possibly useful in other forms of
   secondary pulmonary hypertension as well. The pharmacologic therapy of
   pulmonary vascular disease will be discussed in detail in a subsequent
   lecture.
7. Lung transplantation is often beneficial in patients with primary
   pulmonary hypertension, especially since this disease often afflicts
   younger patients. 5-year survival is about 50-70%, but since waiting times
   are about 2 years for double lung transplants, patients should be referred
   when still in NYHA class 1-2, i.e. symptoms only with moderate exertion. If
   referred when symptoms are present at rest, mean survival may only be
   on the order of 6 months. Complications such as post-operative mortality
   and bronchiolitis obliterans are more common in patients transplanted for
   PPH than for other causes.
OUTCOME OF PATIENTS WITH PULMONARY HYPERTENSION

The development of pulmonary hypertension and right heart failure, or cor
pulmonale, from underlying hypoxic or pulmonary disease represents a late
stage of the illness, and although patients rarely die from the pulmonary
hypertension itself, mortality from advanced respiratory failure is about 90% at 3
years. Pulmonary hypertension from cardiac or congenital shunts may be either
reversible or irreversible, depending on the duration and severity of shunted
blood flow (e.g. a pulmonary to systemic blood flow through a left to right shunt of
> 2:1 is usually associated with severe pulmonary hypertension, but may still be
reversible after anatomic correction, whereas the development of Eisenmenger’s
syndrome usually signifies an irreversible stage of pulmonary hypertension).

Primary pulmonary hypertension is a deadly disease as patients on conventional
therapy prior to the use of prostacyclin were almost uniformly dead in 5 years.
Median survival was 2.5 years. Anticoagulants double the 3 yr survival rates,
Current survival on continuous infusions of prostacyclin is in the order of 50% at
5 years, which compares very favorably with survival after lung transplantation
for this disease. Survival may be even better as more patients are started on
prostacyclin earlier, and indeed many patients have been removed from
transplantation registries because of excellent response to this drug.

Most patients succumb to right sided heart failure, but 7% may experience
sudden death. In terminal stages dilatation of the right heart causes septal
bulging and compromise of LV filling, with congestive heart failure. Balloon
septostomy creates a low resistance shunt from right to left, decompressing the
RV and allowing LV filling, but is seldom used.

Pregnancy often accelerates pulmonary hypertension in patients with PPH, and
is poorly tolerated. Oral contraceptives also exacerbate PPH and are
contraindicated.