CARDIOVASCULAR JOURNAL OF AFRICA • Vol 21, No 6, November/December 2010
334
AFRICA
Review Article
Contemporary insights into the pathogenesis, diagnosis
and therapy of pulmonary arterial hypertension
MOHAMMED R ESSOP
Summary
Current data challenge the concept that pulmonary arterial
hypertension (PAH) is purely a disorder of impaired vasomo-
tor tone. Instead, we recognise today that the phenotype of
PAH represents the complex and disordered regulation of
expression of key signalling molecules and abnormal molecu-
lar trafficking. Discovery of mutations of the ubiquitous
receptors of the transforming growth factor beta (TGF-
b
)
superfamily in many patients with PAH has been instrumen-
tal in unravelling the pathobiology of this otherwise fatal
disorder. Much still needs to be learnt before we are able
to substantially alter the natural history of PAH. Until such
time, therapies that fundamentally attempt to restore vaso-
motor tone continue to be developed and tested.
Current clinical research in the therapeutic arena is
focused on defining the best permutation of the three major
groups of drugs – prostacyclin analogues, phosphodiesterase
type-five inhibitors and the endothelin receptor antagonists.
However, if we are to make any significant impact on the
otherwise dismal outcome of PAH, we have to recognise that
even more important than the challenge of new therapies, is
the challenge in diagnosing the condition early in the course
of its relentless progression to right heart failure and even-
tual death.
Keywords:
pulmonary hypertension, mechanisms, therapy
Submitted 10/5/10, accepted 1/11/10
Cardiovasc J Afr
2010;
21
: 334–337
DOI: CVJ-21.074
Since the first recorded description of pulmonary arterial hyper-
tension by Romberg in 1891,
1
a series of landmark observations
have culminated in a deeper understanding of the pathobiology,
diagnosis and therapy of the disease as we know it today. This
review, compiled by a search strategy of PubMed, using the
terms pulmonary arterial hypertension with specification for
articles published in English, seeks to provide contemporary and
concise answers to the specific questions posed and concentrates
specifically on category 1 (see later) pulmonary hypertension
(PH) under the rubric of pulmonary arterial hypertension (PAH).
For a more general overview, the reader is referred to several
excellent recently published documents on guidelines, classifica-
tion and therapy of PH.
2-5
An increased awareness of PH in South Africa is particu-
larly important for several reasons, all of which have served as
an impetus for the formation of the Pulmonary Hypertension
Interest Group. Firstly, there is reason to believe that PH in
general is a prevalent condition in this country. Apart from the
frequent contribution of valvular heart disease, cardiomyopathy
and congenital heart disease, missed at the time of birth and
during infancy, to the overall burden of PH, preliminary data
from elsewhere suggest that retroviral infection may now be the
leading cause. The incidence of PAH in cohorts of patients with
HIV is estimated at about 0.5%.
4
Even with a conservative preva-
lence of five million people infected with HIV in South Africa,
this would translate to some 25 000 patients with PAH. This
complication is rarely diagnosed, unfortunately carries with it a
poor prognosis independent of the CD
4
count or viral load, and
does not appear to be responsive to highly active anti-retroviral
therapy. Secondly, as in many countries elsewhere, an advocacy
group is sorely required here to promote all aspects of the diag-
nosis and therapy of PAH and importantly, to lobby funders not
to shirk their responsibility toward the management of this small
but desperate group of patients.
What are the pathological hallmarks of PAH?
PAH is a disease of the pre-capillary pulmonary arterial bed,
including the medium-sized pulmonary arteries and pulmonary
arterioles characterised by vascular obliteration. Current knowl-
edge implicates unchecked proliferation of smooth muscle cells
and dysregulated control of endothelial cells with apoptosis and
dysfunction in some areas and profuse proliferation in others.
Plexiform arteriopathy (Fig. 1) is the pathological hallmark of
advanced PAH and represents a chaotic assembly of proliferating
endothelial cells, smooth muscle cells, fibroblasts and possibly
circulating and bone marrow-derived endothelial progenitor
cells. Proximal to these lesions, the pulmonary arterioles are
dilated, have a paucity of endothelial lining, and show prolif-
erative smooth muscle cells, fibroblasts and adventitia. Whereas
distal loss of vasculature was previously thought to be second-
ary to more proximal obstruction, compelling recent evidence
suggests that this may be an active process linked to increased
apoptosis of endothelial cells and pericytes.
5
While pulmonary veno-occlusive disease and pulmonary
capillary haemangiomatosis share some features in common
with other causes of PAH, they are pathologically distinct
and have been included in a separate category termed 1
′
by
the European Society of Cardiology (ESC) and the European
Respiratory Society (ERS) guidelines.
3
Division of Cardiology, Baragwanath Hospital and Univers-
ity of the Witwatersrand, Johannesburg, South Africa, and
Chairman, Pulmonary Hypertension Interest Group
MOHAMMED R ESSOP, MBBCH, MRCP, FCP, FRCP, FACC,
