Pulmonary Arterial Hypertension

Pulmonary hypertension is usually classified as primary (idiopathic) or secondary. It is now

clear, however, that there are conditions within the category of secondary pulmonary
hypertension that resemble primary pulmonary hypertension in their histopathological
features and their response to treatment. For this reason, the World Health rgani!ation
(WH) classified pulmonary hypertension into five groups on the basis of mechanisms, rather
than associated conditions. "he most recent revision of the WH classification uses
consistent terminology and defines pulmonary hypertension more precisely than previous
versions. #roup I of the WH classification, designated pulmonary arterial hypertension, is
the principal focus of this review.
Pulmonary arterial hypertension is defined as a sustained elevation of pulmonary arterial
pressure to more than $% mm Hg at rest or to more than &' mm Hg with e(ercise, with a mean
pulmonary)capillary wedge pressure and left ventricular end)diastolic pressure of less than *%
mm Hg. Pulmonary arterial hypertension comprises idiopathic pulmonary arterial
hypertension (formerly, primary pulmonary hypertension)+ pulmonary arterial hypertension in
the setting of collagen vascular disease (e.g., in locali!ed cutaneous systemic sclerosis, also
,nown as the -./0" syndrome 1calcinosis cutis, .aynaud2s phenomenon, esophageal
dysfunction, sclerodactyly, and telangiectasia3), portal hypertension, congenital left)to)right
intracardiac shunts, and infection with the human immunodeficiency virus (HI4)+ and
persistent pulmonary hypertension of the newborn. "he histologic appearance of lung tissue in
each of these conditions is similar5 intimal fibrosis, increased medial thic,ness, pulmonary
arteriolar occlusion, and ple(iform lesions predominate.
6lthough the pathogenesis of most forms of pulmonary arterial hypertension is un,nown,
there have been many recent developments, especially pertaining to the molecular genetics
and cell biology of idiopathic pulmonary arterial hypertension. In this review, we discuss
these developments and relate them to other forms of pulmonary arterial hypertension, when
appropriate. "reatment is discussed briefly as it relates to the disease mechanism+ more
information on treatment can be found in recent reviews of this topic.
Imbalance of Vascular Effectors
"he main vascular changes in pulmonary arterial hypertension are vasoconstriction, smooth)
muscle cell and endothelial)cell proliferation, and thrombosis. "hese findings suggest the
presence of perturbations in the normal relationships between vasodilators and
vasoconstrictors, growth inhibitors and mitogenic factors, and antithrombotic and
prothrombotic determinants. "hese homeostatic imbalances are probably conse7uences of
pulmonary endothelial)cell dysfunction or in8ury.
Prostacyclin and Thromboxane A
2
Prostacyclin and thrombo(ane 6
$
are ma8or arachidonic acid metabolites of vascular cells.
Prostacyclin, a potent vasodilator, inhibits platelet activation and has antiproliferative
properties+ in contrast, thrombo(ane 6
$
is a potent vasoconstrictor and platelet agonist. In
pulmonary arterial hypertension, the imbalance between these two molecules is shifted toward
thrombo(ane 6
$
5 in the urine of patients with pulmonary hypertension, the levels of a
metabolite of prostacyclin are decreased, whereas the levels of a metabolite of thrombo(ane
6
$
(thrombo(ane 9
$
) are increased. Furthermore, the production of prostacyclin synthase is
decreased in the small and medium)si!ed pulmonary arteries of patients with pulmonary
hypertension, particularly those with idiopathic pulmonary arterial hypertension.
Endothelin-1
/ndothelin)*, a potent vasoconstrictor, stimulates the proliferation of pulmonary)artery
smooth)muscle cells. "he plasma levels of endothelin)* are increased in pulmonary arterial
hypertension, and the level of endothelin)* is inversely proportional to the magnitude of the
pulmonary blood flow and cardiac output, suggesting that these hemodynamic changes are
influenced directly by this vascular effector.
Nitric xide
"he synthesis of nitric o(ide, a potent vasodilator and inhibitor of platelet activation and
vascular smooth)muscle cell proliferation, is cataly!ed by the family of nitric o(ide synthase
en!ymes. :ecreased levels of the endothelial isoform of nitric o(ide synthase have been
observed in the pulmonary vascular tissue of patients with pulmonary hypertension,
particularly those with idiopathic pulmonary arterial hypertension. /ndothelial nitric o(ide
synthase is, however, increased in the ple(iform lesions of idiopathic pulmonary arterial
hypertension, where it probably promotes pulmonary endothelial)cell proliferation.
!erotonin
0erotonin (%)hydro(ytryptamine) is a vasoconstrictor that promotes smooth)muscle cell
hypertrophy and hyperplasia. /levated levels of plasma serotonin and reduced content of
serotonin in platelets have been found in idiopathic pulmonary arterial hypertension and
persist even after the normali!ation of pulmonary)artery pressures following lung
transplantation. 6 platelet defect that results in a reduced upta,e of serotonin (i.e., delta
storage pool disease) has been associated with pulmonary hypertension. 6mong patients who
too, the appetite suppressant de(fenfluramine, which increases the release of serotonin from
platelets and inhibits its reupta,e, for more than three months, the incidence of pulmonary
arterial hypertension increased. .ecently, mutations in the serotonin transporter (%)H""), the
%)hydro(ytryptamine $b receptor (%)H"$9), or both have been described in platelets and lung
tissue from patients with pulmonary arterial hypertension. ;evertheless, the level of serotonin
itself is probably not a determinant of pulmonary hypertension, because selective serotonin)
reupta,e inhibitors (00.Is), which increase serotonin levels but inhibit serotonin transport,
are not associated with an increased incidence of pulmonary hypertension and may, in fact, be
protective in the setting of hypo(ia.
Adrenomedullin
6drenomedullin dilates pulmonary vessels, increases the pulmonary blood flow, and is
synthesi!ed by several cell populations in the normal lung. High levels of messenger .;6
(m.;6) for adrenomedullin and its receptor in the lung suggest a homeostatic role for this
peptide in the pulmonary circulation. "he plasma levels of adrenomedullin are elevated in
both pulmonary arterial hypertension and pulmonary hypertension associated with
hypo(emia, and the elevation correlates with increases in the mean right atrial pressure,
pulmonary vascular resistance, and the mean pulmonary arterial pressure. -urrent data
suggest, however, that increased adrenomedullin is a mar,er of pulmonary hypertension,
rather than a cause.
Vasoacti"e Intestinal Peptide
4asoactive intestinal peptide, a potent systemic vasodilator, decreases pulmonary)artery
pressure and pulmonary vascular resistance in rabbits with monocrotaline)induced pulmonary
hypertension and in healthy human sub8ects + it also inhibits platelet activation and vascular
smooth)muscle cell proliferation. 6 recent study reported decreased levels of vasoactive
intestinal peptide in the serum and the lungs in patients with pulmonary arterial hypertension+
treatment with inhaled vasoactive intestinal peptide improved the clinical course and the
hemodynamics in these patients.
Vascular Endothelial #ro$th %actor
In acute and chronic hypo(ia, the production of vascular endothelial growth factor (4/#F) is
increased and that of its receptors, 4/#F receptor)* (,inase)domain related 1<:.3, or Fl,)
and 4/#F receptor)$ (Flt), in the lung. In pulmonary arterial hypertension, disordered
angiogenic responses appear to underlie the formation of ple(iform lesions and the clonal
e(pansion of endothelial cells within the lesions. 4/#F m.;6 and protein have been
detected in such lesions along with increased amounts of 4/#F receptor)$, hypo(ia)inducible
factor alpha, and hypo(ia)inducible factor beta and decreased amounts of three signaling
molecules essential for the angiogenic response to 4/#F, phosphoinositide)&),inase, 6,t,
and src. "hese observations suggest an abnormal angiogenic response to hypo(ia owing to
abnormal signaling responses in pulmonary arterial hypertension.
In summary, there is an imbalance of the vascular effectors in pulmonary arterial hypertension
that favors vasoconstriction, vascular)cell proliferation, and thrombosis. "he treatments
developed on the basis of these observations (i.e., epoprostenol, nitric o(ide, and endothelin)
receptor antagonists) have been effective in improving the pulmonary vascular
hemodynamics, clinical status, and, in some cases, survival in idiopathic and other forms of
pulmonary arterial hypertension. ;one of these vasoactive molecules, however, have yet been
conclusively lin,ed to the primary pathogenesis of the disease.
Associated En"ironmental %actors
6mong the environmental factors associated with an increased ris, of the development of
pulmonary arterial hypertension, three = hypo(ia, anore(igens, and central nervous system
stimulants = have plausible mechanistic underpinnings.
Hypoxia
Hypo(ia induces vasodilation in systemic vessels, but it induces vasoconstriction in the
pulmonary vasculature. "he acute effect of hypo(ia is regulated, in part, by two endothelial
cell>derived vasoconstrictors, endothelin and serotonin, and, in part, by hypo(ia)mediated
changes in ion)channel activity in smooth)muscle cells in the pulmonary arteries. 6cute
hypo(ia inhibits the function of voltage)gated potassium channels in these smooth)muscle
cells, resulting in membrane depolari!ation, an increase in the concentration of cytoplasmic
calcium, and vasoconstriction. 6cute hypo(ia causes reversible changes in vascular tone,
whereas chronic hypo(ia induces structural remodeling, the proliferation and migration of
vascular smooth muscle, and an increase in the deposition of vascular matri(. 6lthough
hypo(ia is not of central importance in the initial development of pulmonary arterial
hypertension, it may contribute to the remodeling of the pulmonary vasculature as the disease
progresses.
Anorexi&ens
6n association between the use of anore(igenic agents and the development of pulmonary
arterial hypertension was initially observed in the *?@'s, when an epidemic of idiopathic
pulmonary arterial hypertension was noted in /urope after the introduction of the anore(igen
aminore( fumarate. 6lthough this medication was withdrawn from the mar,et, structurally
related compounds, such as fenfluramine and de(fenfluramine, were developed subse7uently,
in the *?A's. "he use of these agents has also been associated with an increased ris, of
pulmonary arterial hypertension. 6lthough the incidence of pulmonary arterial hypertension
increases with the duration of use, an elevation in pulmonary pressure can occur after as little
as three to four wee,s of e(posure to these agents.
'entral Ner"ous !ystem !timulants
"he use of the central nervous system stimulants methamphetamine and cocaine has been
associated with an increased ris, of pulmonary arterial hypertension. 6lthough it has been
suggested that contaminants in synthesi!ed methamphetamine play a causative role,
pulmonary hypertension occurs after the use of contaminant)free fenfluramines and aminore(
fumarate, both amphetamine)li,e anore(igens. In an autopsy study of $' heavy users of
cocaine, the lungs of four showed medial hypertrophy of the pulmonary arteries without
evidence of foreign)body microemboli!ation = findings consistent with pulmonary arterial
hypertension. "he cause of these changes is un,nown, and whether the stimulants alone can
cause pulmonary arterial hypertension is unclear.
/nd of te(t
/(cerpt from a dictionary
A a human blood type of the 69 system, containing the 6 antigen (;"/5 0omeone with
type 6 can donate to people of the same group or of the 69 group, and can receive
blood from people with type 6 or type .)
AA (abbr) 6lcoholics 6nonymous
A ) E accident and emergency department
A ) E medicine the medical procedures used in 6 B / departments
A* a human blood type of the 69 system, containing the 6 and 9 antigens (;"/5
0omeone with type 69 can donate to people of the same group and receive blood
from people with type , 6, 69 or 9.)
A*' the basic initial chec,s of a casualtyCs condition. Full form airway, breathing and
circulation
abdomen a space inside the body below the diaphragm, above the pelvis and in front of the
spine, containing the stomach, intestines, liver and other vital organs
abdomin- prefi( same as abdomino- (used before vowels)
abdominal located in the abdomen, or relating to the abdomen
abdominal aorta noun the part of the aorta which lies between the diaphragm and the point
where the aorta divides into the iliac arteries.
abdominal ca"ity the space in the body below the chest
abdominal distension a condition in which the abdomen is stretched because of gas or fluid
abdominal pain pain in the abdomen caused by indigestion or more serious disorders
abdominal "iscera the organs which are contained in the abdomen, e.g. the stomach, liver
and intestines
abdominal $all muscular tissue which surrounds the abdomen
abdomino- prefi( referring to the abdomen
abdominopel"ic referring to the abdomen and pelvis
abdominoperineal referring to the abdomen and perineum
abdominoperineal excision a surgical operation that involves cutting out tissue in both the
abdomen and the perineum
abdominoposterior ad8ective referring to a position of a fetus in the uterus, where the fetusCs
abdomen is facing the motherCs bac,
abdominoscopy an internal e(amination of the abdomen, usually with an endoscope
abdominothoracic referring to the abdomen and thora(
abducens ner"e the si(th cranial nerve, which controls the muscle which ma,es the eyeball
turn outwards
abducent referring to a muscle which brings parts of the body away from each other or
moves them away from the central line of the body or a limb.
abduct (of a muscle) to pull a leg or arm in a direction which is away from