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Pulmonary Hypertension Primary Pulmonary Hypertension



    Manish J. Patel MD
     Internal Medicine
   Resident Grand Rounds
     February 17, 1998
       HPI: 30 y.o. black female who has had chronic respiratory complaints
for over five years. Originally had been diagnosed with restrictive lung
disease of unknown etiology. From December 1993 to June 1996 the patient
underwent extensive work-up including, rheumatologic studies, sleep
studies, pulmonary function tests, right heart catheterization, ventilation-
perfusion scan, and pulmonary arteriogram, which yielded a diagnosis of
primary pulmonary hypertension. In June of 1996, the patient had an
inhaled nitric oxide test with Swan-Ganz catheter monitoring and was found
to be responsive to vasodilator therapy. She was subsequently started on
Diltiazem and Coumadin. The patient presented to my clinic in March 1997
for Depo-Provera injection. The patient’s weight in Dec. 1993 was 222 lbs.,
but at the time of presentation to my clinic her weight was 300 lbs.
       On physical exam, the patient was extremely obese, had 1+ pitting
edema of both lower extremities, and had a 2/6 tricuspid regurgitation
murmur. She was otherwise unremarkable.
       In the following year, the patient has became more obese (gaining ~70
lbs.), more dyspneic with walking very short distances and spends a majority
of her time in a wheelchair. She is still requesting Depo-Provera injection
when she comes to my clinic.

        Primary pulmonary hypertension (PPH) is a disease of unknown etiology in
which patients have persistent elevation of pulmonary artery pressures that ultimately
lead to right ventricular failure and death. In order to better define the pathophysiology,
epidemiology, natural history, and optimal treatment, the National Institutes of Health
initiated the Patients Registry for the Characterization of PPH in 1981. The registry
consists of 194 patients collected from 32 medical centers over four years. The criteria
used by the NIH in its registry include: 1) a mean pulmonary-artery pressure that is
greater than 25 mm Hg at rest or more than 30 mm Hg with exertion, with 2) the
exclusion of myocardial disease, congenital heart disease, left-sided cardiac valvular
disease, and any clinically important respiratory, chronic thromboembolic, or connective
tissue diseases. 1

         The NIH registry reports the mean age at entry for both men and women as 36.4
years, although nine percent of cases were diagnosed at age 60 or later. In the Japanese
registry the mean age was 31. The registry also showed a female-to-male ratio of 1.7:1
for all ages, which has been supported by most series. This is lower than had previously
been published and may, in part, be due to a reluctance of physicians to make a diagnosis
of PPH in men. In blacks, the female-to-male ratio was 4.3:1 but the distribution by race
was similar to that of the general population (12.3% black and 2.3% hispanic). In
women, the highest incidence was in the third decade and in men, the fourth. Women
tended to have more severe symptoms: 74 percent of women were in the New York Heart
Association Class III-IV compared to 64 percent of men. 2 Six percent of cases in the
registry had a family history of PPH with histopathological and clinical features identical
to the sporadic form of the disease. As expected, these patients tended to have the
diagnosis made earlier in the course of the disease. The pattern of transmission appears
to be autosomal dominant with variable expression. 7

        The vascular resistance seen in PPH is the result of three pathogenic mechanisms:
vasoconstriction, vascular endothelial dysfunction, and thrombosis in situ. The
mechanism of vasoconstriction was first recognized by Dr. Paul Wood, who noted that
patients with pulmonary hypertension would vasodilate in response to an infusion of
acetylcholine. Wagenvoort and Wagenvoort demonstrated that the earliest pathologic
feature of PPH was medial hypertrophy, indicating a stimulus for vasoconstriction and
the proliferation of smooth muscle.8
        Vascular endothelial dysfunction may also play an important role in the
pathogenesis of PPH. Christman et al.4 demonstrated that there was an imbalance in the
ratio of metabolites of prostacycline to metabolites of thromboxane in some patients with
pulmonary hypertension. Thromboxane A2 is a potent pulmonary vasoconstrictor and a
procoagulant whereas prostacycline has opposing effects. They measured the urinary
metabolites of both chemical mediators in 20 patients with PPH, 14 with secondary
pulmonary hypertension, 9 patients with severe COPD but no clinical evidence of
pulmonary hypertension, and 23 normal controls. They found that metabolites of
Thromboxane A2 were increased in patients with pulmonary hypertension compared to
normal controls and patients with COPD without evidence of pulmonary hypertension.
They also found that the metabolites of prostacycline were depressed in these patients.
         Giaid and Saleh5 demonstrated a substantial reduction in the expression of
endothelial nitric oxide synthase in the endothelium of pulmonary vessels of patients with
arteriopathy from pulmonary hypertension, compared to normal lungs. Giaid et. al.6 also
showed that patients with pulmonary hypertension have increased circulating and local
levels of endothelin-1, a promoter of smooth muscle cell proliferation and a potent
vasoconstrictor. Whether these abnormalities are a cause or the result of the disease
remains uncertain.
         Immunocytochemical staining has shown progesterone, but not estrogen,
receptors in the nuclei of the myofibroblasts that form the obstructive pulmonary lesions
in a patient with PPH. Estrogen is known to have a vasodilatory effect and may play a
role in the release of endothelium-derived relaxant factor.15
         Patients with pulmonary vascular disease, regardless of cause, appear to develop
in situ thrombosis within the pulmonary microcirculation as a secondary consequence of
diminished or sluggish blood flow, and injury to the endothelium from high intravascular

        The most common pathologic finding is a plexogenic arteriopathy. Early disease
is associated with smooth muscle hypertrophy and neo-intimal proliferation. With
progression of the disease, there is gradual obstruction with concentric intimal fibrosis,
fibrinoid necrosis, medial hypertrophy and the formation of plexiform lesions.9 Plexiform
lesions are thin-walled, multi-channeled vascular lesions which are thought to develop in
a sequence of vascular wall necrosis, aneurysmal dilatation, local thrombosis,
recanalization and cellular proliferation.10 These features can also be seen in patients
with congenital heart disease, portal hypertension associated with pulmonary
hypertension, and toxin-induced pulmonary hypertension.

       The etiology of PPH is not well understood, however, it has been associated with
a number of exposures, and conditions:
 An appetite suppressant called aminorex (5-amino-5-phneyloxazoline), which is an
    analog of amphetamine, caused an 20-fold increase in pulmonary hypertension in
    Switzerland, Austria and Germany between 1965 and 1968. The pulmonary lesions
    were identical to the plexogenic arteriopathy seen in PPH. The incidence of
    pulmonary hypertension declined to its previous level with the withdrawal of the drug
    from the market.11
   An epidemic of pulmonary hypertension also occurred in Spain in the early 1980s
    with the use of rapeseed (canola) oil in cooking, that was contaminated with aniline
    and acetanilide dyes. In this toxic oil syndrome, most patients died from ARDS.
    Some, however, developed pulmonary hypertension with histologic findings of
    plexogenic arteriopathy.12
   Plant products from crotalaria species, containing pyrolizidine alkaloids, produce
    lesions analogous to those of primary pulmonary hypertension when fed to small
    animals. “Bush tea”, made from another crotalaria indigenous to the Caribbean,
    causes veno-occlusive disease of the liver and a third species has been suspected of
    inducing primary pulmonary hypertension, based on scattered case reports.13
   Patients with eosinophilia-myalgia syndrome from ingestion of contaminated L-
    tryptophan showed similar pathologic findings.
   Hormonal influences may play a role as well. This is demonstrated by the prevalence
    of PPH in young females, the fact that it sometimes presents or accelerates with
    pregnancy 16, and its association with oral contraceptives.14 A report of six cases of
    pulmonary hypertension with associated oral contraceptive use, was published in
    1976. In this report, three women had no discernable predisposition to pulmonary
    hypertension, one woman had a patent ductus arteriosus that had been corrected
    surgically at the age of nine and had mild baseline hypertension, one had lupus, and
    the third had a family history of pulmonary hypertension and clubbing, and was a
   Pulmonary hypertension has also shown some association with portal hypertension 17,
    fenfluramine (4 reported cases)18 , crack cocaine use (4 cases reported), HIV, and
    autoimmune disorders.

       The early diagnosis of PPH is difficult due to the nonspecific nature of the
symptoms. According to the NIH registry, the mean length of time from onset of
symptoms to diagnosis is about two years. Ten percent went undiagnosed for over three
                                                             At the time of
Symptom              Initial complaint %               enrollment in the registry %
Dyspnea                       60                                       98
Fatigue                       19                                       73
Chest Pain                    7                                        47
Near syncope                  5                                        41
Syncope                       8                                        36
Leg edema                     3                                        37
Palpitations                  5                                        33
                                                    Adapted from DR Dantzker 2

Raynaud’s phenomenon, almost exclusively seen in women, was reported in
approximately 10% of patients. Hemoptysis has also been reported, and is thought to be
due to rupture of microvascular aneurysms under high pulmonary artery pressures.
Hoarseness, due to pressure on a laryngeal nerve by an enlarging pulmonary artery has
also been reported. Some authors maintain that chest pain may be related to distension of
the pulmonary artery as well, because its afferents enter the nervous system along the
same pathways as afferents from the heart. Others believe that the chest pain in PPH is
due to variant angina in patients who have generalized vasospastic disease.9

         The physical findings in patients in the NIH registry, was typical of patients with
significant pulmonary hypertension. 93% of patients had a loud pulmonic component of
the second heart sound; 23% had a right-sided S3; 38% had a right-sided S4; 40% had
tricuspid regurgitation and was associated with high right-atrial pressure and low cardiac
output; and 13% had pulmonic insufficiency and was associated with higher pulmonary
artery pressures.2
         Additional findings include a prominent a wave, which is exaggerated by
compression of the liver (Hepato-jugular reflux), cold hands and feet, right ventricular lift
at the left sternal border that is sustained throughout systole, and Graham Steel’s murmur,
which occurs in diastole and is attributed to vibration of the aortic valve leaflet. Cyanosis
is present in 20% of patients, and is usually a late phenomenon. Interestingly, clubbing is
not associated with PPH, and its presence should prompt a search for other causes of
pulmonary vascular disease.9
         Atrial arrhythmias are uncommon and may reflect the patient’s need for an atrial
kick to maintain cardiac output. The occurance of atrial arrhythmias, especially atrial
fibrillation, may precipitate sudden death.

      The differential diagnosis of PPH can be broad and secondary causes of
pulmonary hypertension must be ruled out. The generally accepted work-up includes:

                Echocardiography to rule out congenital, valvular and myocardial
                 disease. It may also give an estimate of pulmonary-artery systolic
                 pressure. In the NIH registry, 75% of patients showed right
                 ventricular enlargement and 59% showed paradoxical motion of the
                 septum. A small end-diastolic left ventricular size was common and
                 was inversely correlated with pulmonary vascular resistance.
                Electrocardiogram revealed right axis deviation and RV strain in
                 >75% of patients in the registry.
                Chest x-ray demonstrated an enlarged main pulmonary artery in 90%,
                 enlarged hilar arteries in 80%, and decreased peripheral vessels in 51%
                 of patients in the registry.
                Interestingly, 6% of patients had a normal CXR, EKG, and ECHO.
                Blood studies can help rule out collagen vascular diseases (although
                 29% of PPH patients have a positive ANA), as well as liver
                abnormalities seen in portal hypertension (which may be associated
                with pulmonary hypertension).19 Arterial blood gases usually show
                mild hypoxemia, out of proportion to pulmonary function
                abnormalities as well as a chronic respiratory alkalosis in patients with
               Pulmonary function tests should reveal normal expiratory flow rates,
                with normal or mildly reduced lung volumes. Typically DLCO is often
                reduced is thought to be due to the obliteration of the small pulmonary
               Ventilation-perfusion scans help rule-out thromboembolic disease. In
                the NIH registry 42% of patients have a normal scan and 77% had
                scans that were described as having diffuse patchy distribution of
                tracer, compared to larger perfusion defects seen in thromboembolic
                pulmonary hypertension.3 Pulmonary arteriography is useful when
                V/Q scans are inconclusive and typically shows the characteristic
                “pruning” of peripheral vessels.
               Cardiac catheterization in patients with PPH, typically reveals
                increased pulmonary-artery pressures to levels three or more times
                normal, elevated right atrial pressure, a reduction in cardiac index and
                a normal pulmonary capillary wedge pressure.2 The normal wedge
                pressure is due to the patency of the larger pulmonary veins and the
                patchy nature of the disease in the veins.3 Patients who were more
                symptomatic had similar pulmonary-artery pressures but had higher
                right atrial pressures and lower cardiac indices. There was no
                difference in degree of pulmonary hypertension between the sexes and
                there was no significant difference in pulmonary pressures as a
                function of duration of symptoms.2

         Therapeutic strategies in the treatment of PPH include vasodilators such as
calcium channel blockers and prostacycline, anticoagulation, transplantation, and
treatment of right heart failure.
         Other strategies include counseling on smoking cessation, oxygen therapy in
hypoxemic patients, and avoiding circumstances that may increase pulmonary artery
pressure and decrease cardiac output. The alveolar hypoxia of high-altitude, such as
flying in commercial aircraft or travel to mountainous regions can exacerbate pulmonary
hypertension. The physician should also avoid using prostaglandin synthase inhibitors
such as indomethacin and sympathomimetic drugs, both of which can cause
vasoconstriction. Drugs that depress cardiac output should also be avoided. PPH is an
absolute contraindication to pregnancy and female patients should practice birth control,
preferably, without oral contraceptives as they may accelerate pulmonary hypertension.
If a patient does become pregnant, termination of the pregnancy should be considered but
abortifacients such as prostaglandin F2, which can increase pulmonary artery pressure,
should not be used.9
        In treating right heart failure all the standard medications may be useful. Digoxin
has been shown to improve right ventricular function only when both right and left heart
failure were present in patients with cor pulmonale secondary to COPD. 20 Digoxin has
also been found to directly increase pulmonary vascular resistance. This effect, in
conjunction with the high incidence of digoxin toxicity has led to a tendency to avoid its
use in PPH. Rich and Brundage, proponents of high-dose calcium-channel blockers in
patients with PPH, have advocated using digoxin in order to offset the negative inotropic
effects of calcium channel blockers. Diuretics are very helpful in patients with right heart
failure due to PPH, but care must be taken to avoid generating a contraction alkalosis
which can, in turn, depress ventilation.19

        Anticoagulation is recommended in all patients with PPH. Anticoagulants are
believed to reduce or halt in situ thrombosis, thereby slowing progression of the disease.
In a prospective non-randomized study of 64 patients, a significant improvement was
observed in patients treated with coumadin (P=0.025). The most marked improvement,
occurred in patients who were categorized as nonresponders to vasodilator therapy.
Survival at 1, 3 and 5 years was 91%, 62% and 47% respectively in the treatment group,
compared to 52%, 31%, and 31% in the untreated group.22

        Vasodilators have been the mainstay of treatment for PPH, based on the
observation that vasoconstriction is a prominent feature of the disease. Unfortunately,
there is no way of predicting which patients will respond to vasodilator therapy without
the use of invasive monitoring. Because of the potential for adverse consequences such
as systemic hypotension, which can lead to myocardial ischemia due to decreased
coronary perfusion, the most suitable drugs for testing acute response are potent, short-
acting and titratable vasodilators such as nitric oxide, epoprostenol (prostacyclin), and
        Rich and coworkers have shown that patients who respond to vasodilator therapy
(defined as > 20% reduction of pulmonary vascular resistance and pulmonary artery
pressure to the acute administration of vasodilator agents) clearly demonstrate improved
survival. In this trial, 17 of 64 patients (26%) had a favorable response to either
nifedipine or diltiazem. At 5 years, 94% of responders were alive compared to 55% of
non-responders. Responders also had fewer symptoms, better exercise tolerance, and
regression of right ventricular hypertrophy. The most widely used and studied drugs for
long-term therapy are nifedipine and diltiazem. Doses as high as 240 mg of nifedipine
and 720 mg of diltiazem may be required to produce benefit in PPH. Verapamil has not
been used due to its negative inotropic effects24 and ACE-inhibitors have also not shown
much benefit in PPH.25
        Monitoring of oral vasodilator therapy can be done with echocardiography and
can be adjusted based on symptoms and physical exam. The side effects of long-term
vasodilator therapy include systemic hypotension, edema, and hypoxemia. Hypoxemia
may be caused by a worsening ventilation-perfusion ratio due to increased perfusion of
poorly ventilated portions of the lung, depression of cardiac output, and shunting of blood
through a patent foramen ovale, if systemic vasodilation is present.3
         Epoprostenol (trade name Flolan), or prostacyclin, has been shown to produce
vasodilation more consistently than calcium-channel blockers. It is a potent vasodilator
of both pulmonary and systemic arteries and has antithrombotic properties due to its
effects on platelets. It had originally been introduced as a bridge to lung transplantation,
but its use has been limited by its short half-life (3-5 minutes), necessitating a continuous
infusion, and tachyphylaxis, requiring increasing doses to sustain hemodynamic benefit.
         In a 12-week prospective, randomized controlled trial of 81 patients, comparing
continuous infusion of epoprostenol plus conventional therapy to conventional therapy
alone, Barst and colleagues, demonstrated significant improvement in survival, symptoms
and hemodynamics in the group receiving the infusion. Exercise tolerance improved in
the 41 patients receiving the infusion and decreased in the conventional therapy group
(P<0.002). Mean changes in pulmonary-artery pressure for the epoprostenol and control
groups were – 8% and + 3%, respectively (P<0.002), mean changes in pulmonary
vascular resistance were – 21% and + 9%, respectively (P<0.001). Eight patients died
during the study, all of whom were in the control group (P=0.003). Complications from
the epoprostenol group included four episodes of catheter-related sepsis and one episode
of thrombosis. Side effects of epoprostenol include headache, cutaneous flushing, jaw
pain and diarrhea. Two patients from the study group were withdrawn. The authors also
noted long-term benefits in patients who did not show acute response to vasodilator
infusion. They had noted this in previous studies as well.26
         In a more recent study, Mclaughlin et al. evaluated the effects of long-term (16.7
+ 5.2 months) epoprostenol infusion in patients with advanced PPH. The dose was
titrated to maximum tolerated, a more aggressive approach than has previously been
used. 27 patients were evaluated, 19 women and 8 men with a mean age of 39.8 years.
At the time of initial evaluation, patients had severe symptoms; 63% were in NYHA
functional class III and 37% were in NYHA functional class IV. At the time of follow-
up, 22% were in NYHA functional class I, 74% in class II, and 4% in class III (P<0.001).
The duration of exercise on treadmill increased by 142% (P<0.001) which did not
correlate with decrease in pulmonary vascular resistance. Patient’s arterial oxygen
saturation was unchanged. At the time of follow-up, cardiac catheterization revealed a
decrease in the mean pulmonary arterial pressure by 22% (P<0.001), an increase in
cardiac output by 67% (P<0.001), and a mean reduction in pulmonary vascular resistance
of 53% (P<0.001).27
         26 of the 27 patients had greater than 20% long-term reduction in pulmonary
vascular resistance. Interestingly, the change in pulmonary vascular resistance after long-
term epoprostenol was not related to pulmonary vascular resistance at base line. Eleven
of the patients received epoprostenol and calcium-channel blockers concurrently and
showed similar results to patients receiving only epoprostenol.27
         This study is the first instance in which a substance produced by normal vascular
endothelium has been used as a treatment for vasculopathy. Their results show that long-
term therapy is not only associated with vasodilation, but also a significant reduction in
pulmonary vascular resistance out of proportion to immediate vasodilation. Experimental
data in animal studies with epoprostanol have shown a potential to reverse vascular
lesions. As pulmonary vascular resistance returns towards normal with long-term use,
patients waiting for transplantation may no longer need it.
         The use of this therapy must take into account the complexity and expense of the
delivery system and the potential for complications. In this series of patients, 10 had a
total of 17 local infections at the exit site of the Hickman catheter and three of these 10
also had positive blood cultures. All were successfully treated with antibiotics. The rate
of local infection was 0.49 per patient-year and blood-borne rate of infection was 0.09 per

         Lung transplantation (single- or double-lung transplant) and combined heart-lung
transplant have been performed for PPH with similar survival rates. Single- and double-
lung transplant is advocated only in patients that fail to respond to pharmacologic agents,
but the timing of transplant is very difficult. Patients must be ill enough to require
surgery, but well enough to survive it. In a review of 109 heart-lung transplants done at
Stanford, survival rates were 68%, 43%, and 23% at one, five, and 10 years,
respectively.28 Mortality rates after transplant are significantly higher among patients
with PPH than patients who had transplant for other indications. Obliterative brochiolitis,
the major long-term complication of transplantation, also occurs more frequently in
patients who received transplant for PPH. PPH is not known to recur in transplant
         Contraindications to lung transplantation include, ventilator dependence (30-fold
increased risk for poor outcome), current or recent presence of malignancy, significant
life-threatening illness, extrapulmonary active infection, marked obesity (weight/height
ratio > 120%) or cachexia (weight/height ratio < 80%), substance abuse, and significant
psychological illness. Relative contraindications include previous thoracic surgery or
pleurodesis and use of corticosteroids prior to transplant. Age is a relative
contraindication with specific cutoffs based on surgical procedure. These cutoffs can
vary from center to center.37

        The estimated median survival of patients in the NIH registry was 2.8 years.
Estimated single-year survival rates were 68% at one year, 48% at three years, and 34%
at five years.
        Survival from time of admission to the registry was related to the New York Heart
Association (NYHA) functional class. Patients in functional classes I and II had a
median survival of 58.6 months, 31.5 months for class III, and six months for class IV.
        Of the hemodynamic variables recorded at baseline, very high correlations with
mortality were seen in elevated mean right atrial pressure, elevated mean pulmonary
artery pressure, and decreased cardiac index.
        Presence of Raynaud’s phenomenon was associated with reduced survival as was
decreased diffusing capacity for carbon monoxide (DLCO).29
        PPH continues to have a poor prognosis, however, treatment strategies such as
calcium channel blockers, anticoagulation and now, long-term prostacyclin infusion are
making surgical options less necessary. Current work in prostacyclin analogs that can be
given orally, transdermally, or by inhalation, may make the continuous infusion system
obsolete, while preserving the benefits.

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