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Pathobiology: Targeting
the Mechanisms of Disease
Clinical and experimental studies have identified potentially
important structural and functional abnormalities,2 but
whether these are cause or consequence of the disease
remains to be determined (Fig. 2). Experimental models
of PPHN have demonstrated that the term “endothelial dysfunction”
does not apply to all aspects of endothelial function,
but to specific sig-nal transduction pathways in certain
segments or regions of the pulmonary vascular bed. Functioning
pathways should be iden-tified and exploited.
Strategies shown to be effective in attenuating the hyper-tensive
response to hypoxia and/or monocrotaline in rats include
endothelin receptor blockers, modulating potassium channels,
inhibition of 5-lipoxygenase as activating protein serine
elast-ase inhibitors,22 inhaled nitric oxide, and inhibition
of 3’5’guanosinemonophosphate-specific phosphodiesterase.
In vitro studies indicate that there will be a role for
smooth-muscle growth inhibitors. The approach to gene
therapy has concen-trated on the overexpression of vasodilator
genes, principally NO and prostaglandin I synthase, and
results are encouraging.23,24 Tackling the different facets
of angiogenesis is problematic. Growth of new vessels
is a priority in the young who have devel-oped pulmonary
hypertension before the lung fulfilled its growth potential.
Intratracheal (VEGF)165 gene injection attenuated hypoxic
pulmonary hyperten-sion in rats, but the mechanism is
uncertain.25 VEGF may not stimulate growth of normal vessels
and in man it is abundant in plexiform lesions, which
some have described as a form of uncontrolled angiogenesis.8
Evidence that advanced disease can be arrested has come
from clinical experience with continuous intravenous prostacyclin
therapy in PPH. Prostacyclin appears to act primarily
by structurally remodeling the pulmonary vasculature rather
than solely as a pulmonary vasodilator. Identifying a
mutation in the BMPR2 receptor implicating defec-tive
control of vascular remodeling puts the structur-al abnormalities
back in the forefront of research interest as being the
prime mover in the pathogene-sis, rather than being viewed
always as the inevitable consequence of endothelial injury.
New therapies will preferentially target the long-term
control of vas-cular remodeling rather than vasoconstriction.
Diagnosis and Clinical
Investigation
In PPH, symptoms vary and are age related.
Infants and young children may fail to thrive, tire easily,
have exertional dyspnea, and, occasionally, chest pain.
Symptoms suggestive of pul-monary hypertensive crises
as well as syncope can occur at any age. The following
tests are crucial:
- Echocardiography, which clarifies intracardiac anatomy
and excludes congenital heart disease. Estimation of
the pulmonary arterial pressure, right atrial and ventricular
cavity size, and ventricular function is essential.
- Exercise test, a 6-minute walk test or surrogate according
to age and capacity, to measure the degree of functional
impairment. In PPH exercise capacity correlates with
right atrial pressure, pulmonary arterial pressure,
and cardiac index.
- Pulmonary function tests.
- Oxygen saturation measurements, including a sleep
assessment.
- Cardiac catheterization: Following a conventional
study, acute vasodilator testing is carried out using
100% oxygen and short-acting vasodilators, such as inhaled
nitric oxide, intravenous epoprostenol, and intravenous
adenosine. Using measured oxygen consumption together
with arteri-ovenous oxygen difference, cardiac output
is calculated and pulmonary vascular resistance determined.
A positive response to acute vasodilator testing means
reducing the pressure and resistance to a value approaching
normal in the presence of an unchanged or increased
cardiac out-put. Atrial septostomy/septectomy should
be considered at the time of diagnostic catheterization
in severely ill children (particularly if there is a
history of drop attacks) whose anatomy is such that
there is no opportunity for right to left shunting to
acutely decompress the right heart and improve systemic
output. An open lung biopsy may be indicated in complex
congenital heart disease, suspected venoocclusive disease,
and vasculitis.
Tests carried out primarily to detect chronic thromboembol-ic
disease are rarely indicated in childhood.
Management of the Pulmonary
Hypertensive Child
In patients with PPH treated with chronic vasodila-tor
therapy the most important determinants of sur-vival are
(1) age, with a 5-year survival of 88% in children of
less than 6 years of age, as compared with 25% for older
children and (2) the acute response to prostacyclin, the
5-year survival being 86%, as compared with 33% for nonresponders.26
In congenital heart disease, symptoms and signs reflect
the natural history of pulmonary vascular dis-ease with
and without surgery in the different anom-alies. Lessons
learned in the management of chil-dren with PPH are now
being applied to other forms of pulmonary hypertension
in childhood.
PPH
Treatment for PPH is lifelong. The therapeutic regi-men
has to be individualized and adjusted accord-ing to changes
in clinical and hemodynamic status. Children need close
monitoring of the clinical course to ensure a satisfactory
and sustained response to treatment, with recatheterization
if necessary. Optimizing the management of these patients
markedly improves quality of life and survival. The principles
of manage-ment are:
- Children with a positive response to acute vasodilator
test-ing are given calcium channel blockers, usually
nifedipine. Actuarial survival is increased in adults
treated with this drug. But the magnitude of response
that predicts long-term survival is unknown in the young,
and repeat cardiac catheterization is necessary after
several months to detect any deterioration. Loss of
acute responsiveness demands urgent revision of therapy.
- Children unresponsive to acute vasodilator testing
are not treated with calcium channel blockers, which
can have adverse effects and precipitate or worsen right-heart
fail-ure. Older, compliant children in NYHA Class II
can take nebulized iloprost, which has a similar molecular
structure to epoprostenol. Regular, effective dosing
(6-12 times a day) is difficult in young children. The
dual endothelin receptor antagonist Tracleer (bosentan),
efficacious in adults, is now being studied in children.
The oral prosta-cyclin analogue beraprost sodium is
efficacious in adults but recommended only for those
with less severe pul-monary hypertension and is largely
untested in children. The subcutaneous analogue of prostacyclin,
treprostinil (Remodulin), is too painful for use in
young children. The phosphodiesterase inhibitor sildenafil
is untested, but its effect appears to be relatively
short-lived in sick children. The proven treatment of
choice for the very sick child is long-term intravenous
epoprostenol (Flolan). The dose is titrated according
to clinical response, subjective and objective. Children
generally need much higher doses of epoprostenol than
adults and can become very tolerant of the drug, requiring
constant, aggressive, upward adjust-ment of their dosage.
Despite the obvious logistical prob-lems, infants and
young children can be managed satis-factorily. The side
effects experienced by children are similar to those
seen in adults.
- Supplemental domiciliary oxygen provides symptomatic
improvement for those with sys-temic arterial desaturation.
- Anticoagulation: Warfarin rather than aspirin or dipyridamole
is recommended to prevent thrombosis in situ, although
aspirin is more tol-erable in early infancy.
- Supportive medical therapy: Diuretics are indi-cated
to control the fluid retention of right-heart failure
but should be administered cautiously in very sick children,
who need a high preload. Digoxin may be helpful in the
treatment of right-heart failure.
- Atrial septostomy/ septectomy, if indicated.
- Organization of care in the community and con-tact
with patients’ support groups is essential.
Screening and Genetic Testing. All first-degree relatives
are screened in FPPH. It is thought that an individual
in a family with FPPH has a 5% to 10% lifetime risk of
developing PPH.27 Genetic testing entails DNA sequencing
because mutations in the BMPR2 gene appear to be “private”
to each family.
Congenital Heart Disease
Correlating the physiological findings
with structural observa-tions in different types of intracardiac
abnormality has improved the accuracy with which immediate
and long-term outcome can be predicted with and without
corrective surgery.28 But prediction is still more difficult
in younger children. The most crucial factor in determining
late outcome is the age at which repair is carried out.
Most children operated on by 9 months of age have a normal
pulmonary vascular resistance one year after repair. After
two years of age-resistance may fall, but not to a normal
level. These observations indicate vessel wall remodeling
toward normality, continued growth, and a demon-strable
improvement in endothelial function.18 Repairing an intracardiac
abnormality in the presence of established disease accelerates
the progression of disease and the onset of right ventricular
failure and death. If there is doubt about the likely
outcome of surgical repair, then an open lung biopsy should
clarify the position.
Treatment for patients with classic Eisenmenger syndrome
is empirical. Long-term oxygen treatment often gives subjective
improvement. Dipyridamole is thought to reduce platelet
aggre-gation but may also have a beneficial vasodilatory
effect as a phosphodiesterase inhibitor. Anticoagulation
is recommended. Phlebotomy with plasma dilution in those
with a high hemat-ocrit is not used routinely but may
afford symptomatic relief to some patients. Frequent phlebotomy
causing iron deficiency can increase the risk of cerebrovascular
accidents.
Treatment with prostacyclin is tempting, but its efficacy
is not proved in patients with classic Eisenmenger syndrome
and it can cause systemic hypotension in the presence
of pulmonary-systemic communication. Endothelin receptor
antagonists are promising but still unproved therapies.
Long-term administra-tion of L-arginine might be helpful
if it could be shown conclu-sively that these patients
have a relative substrate deficiency of NO production.
Calcium channel blockers are not used.
Finally, the only effective treatment for the very sick
patient with pulmonary vascular disease of any etiology
who has failed medical treatment is lung transplantation.
This is not usually an option in young children. Since
the results of lung transplan-tation are less than optimal,
transplantation should be considered only when the expected
survival on medical treatment is less than the expected
survival after transplantation. In the future, we can
hope that prompt early referral and effective treatment
with the new and emerging therapies will postpone the
need for transplantation indefinitely in many young people.
Future Treatment Strategies
- Maximize the effect of current therapies by inves-tigating
selective combinations of drugs for use at different
stages of disease.
- Elucidate the role of endothelin receptor antagonists
and the extent to which they can replace or be used
with intra-venous prostacyclin and the different prostacyclin
ana-logues.
- Develop new, stable prostacyclin analogues with a
longer half-life for oral and inhalational use and specific,
long-acting phosphodiesterase V inhibitors.
- Explore novel therapies, such as elastase inhibitors,
gene therapy, and treatments based on exploitation of
key sig-naling pathways identified by BMPR2 mutations
in FPPH.
- Stimulate growth of new, normal vessels, particularly
in the young.
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