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Chapter 14
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Pulmonary Hypertension
Massimiliano Mulè, Giulia Passaniti and Daniela Giannazzo
Abstract
Pulmonary hypertension (PH) is a complex and multifactorial syndrome, partly
unknown, characterized by a profound alteration of pulmonary vasculature and,
consequentially, a rise in the pulmonary vascular load, leading to hypertrophy and
remodeling of the right heart chambers. The World Health Organization assembles
the several forms of PH into five clinical groups: group 1 includes pulmonary arterial
hypertension, previously defined as idiopathic forms, group 2 is PH due to left-sided
heart diseases, group 3 PH due to lung diseases, hypoxia, or both, group 4 due to
pulmonary-artery obstruction, and group 5 PH, which includes forms with multifactorial or unclear mechanisms. In this chapter, we would like to delineate the clinical
and hemodynamic definitions of PH and, for each group, we will describe the pathophysiological mechanisms, the diagnostic pathway, and the pharmacological approach
and treatment. Finally, we would also like to focus on the latest trials and future
therapeutic perspectives for this disease.
Keywords: pulmonary hypertension, pulmonary arterial hypertension, right heart
failure, right heart catheterization, pulmonary circulation
1. Introduction
Pulmonary hypertension (PH) is a complex and multifactorial syndrome, partly
unknown, characterized by a profound alteration of pulmonary vasculature and,
consequentially, a rise in the pulmonary vascular load, leading to hypertrophy and
remodeling of the right heart chambers.
1.1 Basic principles of pulmonary circulation
Pulmonary circulation, includes a vast network of arteries, veins, and lymphatic
vessels and is unique, both in function and volume: it is a low-pressure, low-resistance,
highly distensible system, and it is capable of accommodating large increases in blood
flow with none or minimal elevations of its pressure. During embryonic life, the pulmonary circulation is a low-flow and high-resistance circuit. After birth, once the baby
takes his first breath, the high resistance in the lungs drops dramatically: from now on,
blood can enter lungs for oxygenation. Oxygen relaxes the pulmonary vessels and
causes closure of the fetal shunts: at this precise moment, the baby’s blood flow is
identical to that of an adult [1]. Therefore, this vasculature dilates, in order to take in
the entire cardiac output (CO), with high blood flow at low intravascular pulmonary
arterial pressure (PAP). Anatomically, pulmonary arteries have thinner walls with less
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smooth muscle and lack of basal tone: this happens because of the elevated production
of endogenous vasodilators and low production of vasoconstrictors from the endothelium of the pulmonary vessel walls. These mechanisms result in the maintenance of a
normal pulmonary vascular resistance (PVR) [2]. Pulmonary circulation differs functionally from the systemic one because it carries mixed venous blood. Deoxygenated
blood is channeled through the pulmonary artery directly in the alveolar/capillary units
where gas exchange occurs and blood releases carbon dioxide and is replenished with
oxygen. Then, oxygenated blood is carried back to the left atrium by the pulmonary
veins, in order to be distributed to the systemic circulation.
1.2 Physiological bases of hemodynamic classification
In order to better understand the hemodynamic classification of PH, we should
recall Poiseuille’s law, one of the most important laws of fluid dynamics (1):
Q ¼ P
1
2
P
ðÞπr4=8μl (1)
Where Q is flow (l/min) and then Cardiac Output (CO), if we apply the equation
to the pulmonary circulation; P
pressure at the beginning of the pulmonary circulation, P
is mean pulmonary arterial pressure (mPAP), the
1
is the pulmonary artery
2
wedge pressure (PAWP) equivalent to the left atrial pressure, the pressure at the end
point of the pulmonary circulation, when measured at right heart catheterization
in the absence of pulmonary vein stenosis. 8μl/πr
4
is a measure of the pulmonary
vasculature resistance (PVR).
According to Poiseuille’s law, pulmonary vasculature resistance (PVR) is inversely
related to the fourth power of arterial radius: in this equation, l represents the length
of the vessel, r its radius, and μ the viscosity of the fluid, in our case, blood. PVR is
used to characterize PH because this parameter allows us to quantify abnormalities of
the pulmonary vasculature, as it is mainly related to the anatomical geometry of small
distal arterioles of the lung. PVR can also be expressed as (2):
Therefore, PVR reflects the functional status of pulmonary vascular endothelium/
smooth muscle cell coupled system, and it is also positively related to blood viscosity.
Additionally, PVR may be influenced by changes in perivascular alveolar and pleural
pressure. According to Poiseuille’s law mPAP depends on cardiac output, left atrial
pressure, and PVR (3)
whereas pressure does not depend on the size of the body, and PAP from different
patients can be evaluated without considerable differences in their body size [3, 4].
PAWP is an acceptable estimate of left atrial pressure (LAP) or left ventricular enddiastolic pressure (LVEDP) in the absence of mitral stenosis or pulmonary vein stenosis. Furthermore, PAWP and LVEDP are usually considered to be interchangeable,
even if some pathological scenarios, such as atrial fibrillation, rheumatic disease, or
large diameter of the left atrium are associated with a PAWP higher than LVEDP.
PAWP and LVEDP measurements should be obtained at the end of the expiratory
phase and the end of the diastolic phase, QRS gated [4].
2
PVR ¼ mPAP–PAWPðÞ=CO (2)
mPAP ¼ CO PVRðÞþPAWP (3)
Pulmonary
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2. Haemodynamic
classification of PH
According to the European Society of Cardiology 2015 guidelines, PH is defined as
an
increase in mean pulmonary arterial pressure (mPAP) ≥25 mmHg at rest as
by
assessed
normal
20
mmHg [5]. This definition was updated at the sixth world symposium of PH, held
2018 in Nice: the mPAP threshold was lowered from ≥25 to >20 mmHg [6].
in
Whatever
emphasize
does
depends
right heart catheterization (RHC). Available data have shown that the
mPAP at rest is 14 3 mmHg with an upper limit of normal of approximately
the mPAP cut-off value considered for defining PH, it is important to
that this value used in isolation cannot characterize a clinical condition and
not define the pathological process per se. According to Poiseuille’s law mPAP
on
cardiac output, left atrial pressure, and PVR (4).
mPAP
¼
ðCO PVRÞ þ PAWP
(4)
Then, mPAP elevation may have several different causes with different prognoses
treatments, including high cardiac output syndromes (anemia, lefttoright
and
shunts,
heart
precapillary
namically
elevation
AV
fistula, and thyrotoxicosis.) or diseases characterized by high PWAP (left
diseases) or high PVR because of pulmonary vascular disease [6]. Specifically,
pulmonary hypertension due to pulmonary vascular disease is hemody-
defined by a pulmonary artery wedge pressure (PAWP) ≤15 mmHg and an
in
PVR of at least three wood units (WU).
Precapillary hypertension contrasts with postcapillary PH in which the PVR is less
than
3 WU
and the elevation in the mPAP is due to elevated filling pressures on the
left
side of the heart (PAWP
> 15
mmHg) [7].
Postcapillary PH is further subclassified on the basis of the PVR, into isolated
postcapillary
post-capillary
PH
PH
(PAWP
(PAWP
> 15 mm Hg
> 15 mm Hg
and PVR
< 3
WU) and combined pre- and
and PVR ≥ 3 WU). (See Table 1).
3. Clinical
classification of PH
Besides the haemodynamic classification, the clinical classification of PH is rele-
and very helpful to choose the appropriate therapeutic pathway and, consequen-
vant
estimate the prognosis of patients. Since the first world symposium of PH held
tially,
Definitions Characteristics
mPAPPre-capillary PH > 20 mmHg
PAWP ≤ 15 mmHg
PVR ≥ 3WU
mPAPIsolated post-capillary PH > 20 mmHg
PAWP > 15 mmHg
PVR < 3WU
mPAPCombined pre- and post-capillary PH > 20 mmHg
PAWP > 15 mmHg
PVR ≥ 3WU
Table 1.
Haemodynamic classification of PH.
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in 1973, the clinical classification has been reviewed many times: in fact, due to the
remarkable spread of PH in the last 40 years, new scientific pieces of evidence have
been discovered, leading to a necessary update in the classification. The actual clinical
classification was defined by the World Health Organization in 2018, during the Sixth
World Symposium in Nice and it includes five major groups, classified according to
similar clinical presentation, pathological findings, hemodynamic features, and
treatment approaches (see Table 2).
Specifically, each group includes:
• Group 1: Pulmonary arterial hypertension (PAH)
• Group 2: PH due to left-sided heart disease
• Group 3: PH due to lung disease, hypoxia, or both
• Group 4: PH due to pulmonary artery obstruction
• Group 5: PH with multifactorial or unclear mechanisms
Making a correct diagnosis of PH is very complex, challenging, and timedemanding, and it can only be made in high expertise centers by a multidisciplinary
team of cardiologists, pneumologists, radiologists, and rheumatologists. Diagnostic
tools, include EKG, echocardiogram, blood tests analysis, pulmonary function test
with diffusing lung capacity test for carbon monoxide, high-resolution CT scan, lung
ventilation/perfusion scan, and right heart catheterization (RHC). RHC represents the
gold standard for the final diagnosis: while performing it, the expert specialist should
also complete the procedure, including a vasoreactivity test with short-acting selective
vasodilators agents, in order to predict if patients will respond to treatment. At this
point, after ruling out any other causes of increased mPAP, the diagnosis of PAH can
be made, as it is a diagnosis of exclusion.
We will now analyze the various groups of PH based on their prevalence.
3.1 PH associated with left heart diseases (group 2)
3.1.1 Epidemiology
Due to the prevalence of left heart diseases in the general population, group 2 PH
represents the most prevalent form of PH, responsible for 65% of PH cases [8].
Mostly, it is associated with heart failure (HF), but it can also be a complication in
patients with left-side heart valvular and congenital diseases. The exact prevalence of
PH is still not known because of variabilities in PH definitions with predominant
echo-based literature data and referral bias. It has been estimated that about 60% of
patients with heart failure with reduced ejection fraction (HFrEF) have pulmonary
hypertension at presentation, while in patients with left ventricular diastolic dysfunction the prevalence of PH is 83% [8, 9].
3.1.2 Pathophysiology
The pathophysiology of this type of PH is multifactorial but mainly based on the
effect of the hydrostatic pressure on the pulmonary vasculature, resulting in its
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3. PH due to lung diseases and/or hypoxia1. Pulmonary arterial hypertension (PAH)
3.1 Obstructive lung disease1.1 Idiopathic PAH
3.2 Restrictive lung disease1.2 Heritable PAH
3.3 Other lung disease with mixed restrictive/1.3 Drug- and Toxin-induced PAH
obstructive pattern
3.4 Hypoxia without lung disease1.4 PAH associated with
3.5 Developmental lung disorders1.4.1 Connective Tissue Diseases
1.4.2 HIV infection
1.4.3 Portal Hypertension 4. PH due to pulmonary artery obstruction
4.1 Chronic thromboembolic PH (CTEPH)1.4.4 Congenital Heart Disease
4.2 Other pulmonary artery obstructions1.4.5 Schistosomiasis
1.5 PAH long-term responders to calcium channel
blockers
1.6 PAH with overt features of venous/capillaries (PVOD/
PCH) involvement
2. PH due to left heart diseases 5.2 Systemic and metabolic disorders
2.2 PH due to heart failure with preserved LVEF (HFpEF) 5.4 Complex congenital heart diseases
2.3 Mitral and/or Aortic valve diseases
2.4 Congenital or acquired cardiovascular conditions
leading to post-capillary PH
5. PH with unclear and/ or multifactioral
mechanisms
5.1 Hematological disorders1.7 Persistent PH of the newborn syndrome
5.3 Others2.1 PH due to heart failure with reduced LVEF (HFrEF)
Table 2.
Updated clinical classification of pulmonary hypertension, according to the 6th PH world symposium of 2018,
Nice, France.
change and remodeling. Both types of cardiac heart failure (preserved and reduced
ejection fraction), other than valvular disease and congenital heart disease can lead to
a passive increase of pressure in the left atrium (LA), and consequently, a decrease in
its compliance. The LA has a key role in maintaining normal pulmonary pressure
because it constitutes the connection between pulmonary circulation and systemic
circulation, through the left ventricle [9]. Any increase in the LA pressure even mild
perturbates the pulmonary hemodynamics. According to the Poiseuille’s law, the
increase of pressure in the LA, the end point of the pulmonary circulation (P
), will
2
results in a proportional increase of the pressure at the beginning of the pulmonary
circulation (P
), to maintain the forward flow; therefore, the increase of LA pressure
1
will result in a proportional and passive increase of the mPAP. In addition, the
increased pressure transmitted back to the pulmonary vasculature promotes significant changes in the structural anatomy. The raised backward pressure causes lung
capillary and small artery stress, as the barotrauma breaks the endothelial layer and
promotes fluid and protein swelling in the interstitium. Therefore, the intimal layer
undergoes fibrosis and the tunica media undergoes hypertrophy [10]. In this setting,
the endothelium plays a central role in the local control of tone through the regulated
release of nitric oxide (NO) and endothelin (ET): the dysregulation of pulmonary
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vascular tone involves alterations in these important counterbalancing systems, causing a decrease in the production of endogenous vasodilators NO and an increase in
vasoconstrictors ET [10, 11].
The transition from alveolar-capillary stress failure to remodeling is clinically
reflected by the rise of PVR in patients with long-standing post-capillary PH who
develop combined pre- and post-capillary PH.
3.1.3 Impact on prognosis and clinical picture
PH due to left heart disease results in severe symptoms and worse exercise
tolerance and exerts a negative impact on outcome with an evident poor prognosis.
These patients are usually elderly, with a high prevalence of cardiovascular
co-morbidities, such as obesity, hypertension, atrial fibrillation, diabetes, coronary
artery disease, kidney disease, and metabolic syndrome [12]. The patient usually presents with symptoms related to left heart diseases, such as fatigue, exertional dyspnea,
orthopnea, paroxysmal nocturnal dyspnea, and peripheral edema. The medical history
can reveal a previous diagnosis of heart failure, systolic or diastolic, myocardial
infarction, systemic arterial hypertension, or valvular disease (frequently mitral
regurgitation). Findings of physical examination, include left-sided gallops, left-sided
murmurs (particularly mitral), a displaced or sustained apical impulse, and pulmonary crackles in cases of pulmonary congestion. PH may be a cause of morbidity and
mortality in patients with chronic heart failure; death and hospitalization for heart
failure are greatly increased in patients with echocardiographic evidence of PH [13].
Apparently, PH has a major impact on right ventricle function, and this is a strong
predictor of overall and event-free survival in chronic heart failure patients [14].
3.1.4 Therapy
After the diagnosis is made, the primary need is to start a therapy that has to focus
on the global management and improvement of the underlying conditions, before
treating the PH; lowering filling pressures in left-heart cavities is the goal of treatment
in many forms of group 2 PH.
This can include percutaneous repair or surgery of the valvular heart disease and
optimal pharmacological therapy for HF with reduced systolic function [15]. Other
cardiovascular risk factors, such as hypertension, dyslipidemia, diabetes, and obesity
should be maintained under strict control. In the past years, many trials have been
conducted in order to evaluate specific PAH therapies in treating group 2 PH patients:
these studies were based on the idea that PH is due to a misbalance between the
production of NO and ET. So, it has been supposed that ET receptor antagonists,
prostanoids, and phosphodiesterase-5 inhibitors (PDE5-i) can play a role in slowing
down the progression of the disease. Several trials were completed using prostanoids
and ET receptor antagonists, but none of them have demonstrated the superiority of
these treatments in terms of decrease in disease progression or increase in overall
survival [16].
3.2 Pulmonary hypertension associated with lung diseases
PH associated with hypoxia and lung diseases is the second most common form of
PH worldwide. It is associated with various lung diseases, such as chronic obstructive
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pulmonary
(OSA),
disease (COPD), interstitial lung disease (ILD), obstructive sleep apnea
and, less frequently, cystic fibrosis [17] and high altitude exposure [18].
PH has a different prevalence in each of the cited lung diseases. Numerous studies
patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage
in
revealed that up to 90% of these patients have a mPAP >20 mm Hg [19]. The
IV
prevalence
disease
values
30%
3.2.1
of PH in
and the severity of the disease: in idiopathic pulmonary fibrosis (IPF), mPAP
>20 mmHg was reported 8–15% of patients. Higher percentages, ranging from
to
50%, are found in advanced and end-stage (>60%) IPF cases [20].
Pathophysiology and differences of PH associated with COPD and ILD
patients with ILD varies greatly according to the underlying
The pathogenesis of the vascular remodeling correlated to COPD has not been fully
clarified
dysfunction
tion,
indirect
channels
the
inducible
vasoconstriction,
different
injury
consequently
growth,
Specifically,
tric
adventitia
cells
strate
changes,
the
but appears to be caused by the mutual effects of hypoxia, pulmonary
with air trapping, and the toxic effects of smoking, leading to inflamma-
endothelial dysfunction, and angiogenesis [21]. Hypoxia has both a direct and an
effect on pulmonary circulation remodeling: directly, it closes potassium
of
the smooth muscle cells, causing their contraction; indirectly, it acts on
genesis and the production of inducible transcription factors, such as hypoxia-
factor-1 (HIF-1), angiotensin II, and more growth factors that have a role in
vascular remodeling, and neo-angiogenesis [22]. PH in ILD has a
pathogenesis: according to the latest scientific evidence, a recurring stress
leads to impairment of epithelial cells and basement membranes, and this is
followed by exudation of fibrin and focal fibroblast activation and
resulting in fibrotic remodeling of lung parenchyma and pulmonary vessels.
all layers of the muscular pulmonary arteries show concentric and eccen-
remodeling. Widespread hyperplasia is present in the intimal layer, media, and
layers are thicker due to hypertrophy and/or hyperplasia of smooth muscle
and fibroblasts, respectively [23]. Non-muscularized pulmonary arteries demon-
neo-muscularization of the media and luminal narrowing. In response to these
capillary density increases in normal, non-fibrotic areas of the lungs, while in
fibrotic area of the lungs, there is vascular regression [24].
An interesting concept has been presented by Mura et al.: they were one of the first
groups
In
tiate
PH
severe
This
patients,
opment
mechanisms
from
tion
lar
to
compare gene expression with microarray in the lungs of patients with IPF.
this innovative study, the writers defined particular gene signatures that differen-
IPF patients with and without PH. The authors found that IPF patients without
predominantly had a pro-inflammatory gene expression, while IPF patients with
PH
(mPAP
study establishes a strong molecular difference between these two groups of
supporting the hypothesis of specific pathway activation during PH devel-
in
IPF patients [25]. Finally, with increasing evidence on certain molecular
a
“passive state”, where PH development was only due to hypoxic vasoconstric-
and loss of vascular bed density, to an “active process” where particular molecu-
and cellular pathways are involved [24].
> 40
mmHg) had a pro-proliferative gene signature expression.
driving PH development in IPF patients, the paradigm is slowly changing
PH can also be due to chronic up-regulation of hypoxic pulmonary vasoconstric-
caused by long-term exposure to high altitudes. This particular type of PH affects
tion,
people
pulmonary
to
residing at an altitude of 2500 meters or higher. The hypoxic stimulus leads to
vasoconstriction and, consequently, a rise in vascular resistance, in order
decrease perfusion of non-ventilated lung areas and increase blood flow to
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better-oxygenated areas. Scientific data suggests that genetics plays a role in PH
predisposition, but the mechanisms are not clearly understood [18].
3.2.2 Impact on prognosis and clinical picture
PH is a poor prognostic indicator of chronic lung disease. Comparing the 5-year
survival rate in patients with COPD, the survival is 36% in patients with PH, compared to the 62% in patients without PH [19]. Patients can present with a variety of
symptoms, including shortness of breath, fatigue, cough, reduced exercise capacity,
and syncope. Physical examination shows a louder second heart sound with a fixed or
paradoxical splitting. Also, a systolic ejection murmur, increased by inspiration, may
be heard over the left sternal border. Severe PH eventually leads to right ventricular
failure with signs of systemic venous hypertension: this clinical condition was known
as core pulmonale. The signs of right ventricular failure, include a high-pitched systolic murmur of tricuspid regurgitation, hepatomegaly, a pulsatile liver, ascites, and
peripheral edema.
3.2.3 Therapy
Given the morbidity and mortality associated with PH in pulmonary diseases,
there has been great interest in the treatment of these patients with pulmonary
vasodilator therapy.
However, nowadays there are still no approved therapies for group 3 PH. In the
last few years, many trials have been carried out, in order to examine and analyze if
drugs approved for other forms of PH can play a role in the therapeutic pathway of
these patients, with conflicting results. In addition to the lack of positive results in
terms of prognosis, concerns have been raised about the potentially negative effect of
pulmonary vasodilator therapy in worsening hypoxemia due to uncoupling of the
ventilation/perfusion (V/Q) ratio in lung diseases. A few studies showed positive
effects of pulmonary vasodilators, in the absence of worsening hypoxemia. For example, the SPHERIC-1 (Sildenafil and Pulmonary HypERtension In COPD), explored if
Sildenafil can lower PVR and improve the quality of life of group 3 patients. After
16 weeks, the results were that sildenafil safely improved PVR, CO, and symptoms
(evaluated with BODE score), in selected patients with COPD-associated severe PH
[26]. In patients with ILD, several trials with pulmonary vasodilators have shown
detrimental effects of these drugs in terms of symptoms and survival (i.e.,
Ambrisentan or Riociguat). Positive results have been shown in a randomized controlled trial involving 326 ILD-PH patients, randomized to inhaled treprostinil or
placebo: in the inhaled treprostinil group, there was an improvement in exercise
capacity, assessed with 6-min walking test [27]. However, more data from larger trials
are needed to approve this therapy for COPD- or ILD- PH patients. Currently, therapy
for group 3 PH is primarily directed at the treatment of the underlying disease, with
general supportive therapy when right ventricular failure develops.
3.3 Pulmonary arterial hypertension
3.3.1 Epidemiology
Group 1 PH (or PAH) is a rare, highly complex, and progressive disorder that is
incurable and ultimately can lead to premature death. PAH causes noteworthy
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physical,
social, work, and emotional burdens among affected patients and their
caregivers.
PAH affects from 15 to 50 people per million within the United States and Europe,
and
it
usually affects women between 30 and 60 years of age [28]. However, it can
occur
in
males and is often associated with worse clinical outcomes. The National
Institutes
1981
pathic
participants
34%)
Term
the
individuals
established
the
including
change in the PAH population cohort [30].
a
3.3.2
of
Health (NIH) was an important registry that collected PAH data between
and 1985: it included 187 individuals, mostly Caucasian females, having idio-
PAH. PAH-specific therapies were not available at that time, and registry
had a median survival of 2.8 years (1 year, 68%; 3 years, 48%; and 5 years,
[29]. Another milestone registry is the Registry to Evaluate Early and LongPAH Disease Management (REVEAL), performed between 2006 and 2009 in
USA: results of this registry showed a 1-year survival rate of 91% among 2716
who were enrolled. A supplementary analysis assessing long-term survival
survival rates of 85% at 3 years, 68% at 5 years, and 49% at 7 years from
time of diagnosis. The increases in survival rates were ascribed to several reasons,
availability of specific drugs, improved patient support, and hypothetically,
Pathophysiology
Group 1 PH includes many subgroups, such as idiopathic, heritable, drug, and
toxin-induced,
HIV infection, portal hypertension, congenital heart disease, and schistosomia-
eases,
sis.
However, regardless of the primary conditions, patients show similar
pathophysiological
endothelial
situ
thrombi [31]. These lead to an increase in PVR, an increase in mPAP, and,
consequently,
compensates
remodeling,
persistent
right
ventricle to adapt to this afterload is the key element in developing symptoms
determining survival, and eventually, it is the failure of the right ventricle that is
and
the
main cause of death in patients with PAH (Figure 1). Nowadays, three main
pathways
(ET1),
and Prostacyclin (PGI
vasodilator
enzyme, by converting L-arginine into L-citrulline. In PAH, there is a notable
tase
decrease
smooth
lets’
potent
Its
muscle cells, inflammation, and finally thrombosis, due to the lack of plate-
anti-aggregation properties. ET1 is a peptide produced by endothelial cells; it is a
vasoconstrictor that stimulates smooth muscle cell division and proliferation.
levels rise in the pulmonary and systemic circulation of PAH patients and its value
negatively
arachidonic acid in the endothelium: its actions are similar to the NO ones,
from
including
inhibiting
which
counteracts its effects. In normal conditions, the quantities of these two pep-
are in balance; instead, in PAH patients, there is an imbalance between the
tides
and PH associated with other diseases such as connective tissue dis-
pathways, such as augmented pulmonary arterioles contractility,
dysfunction, proliferation of smooth muscle cells, and the presence of in
a
raise in right heart afterload. Although the right ventricle initially
for this augmented afterload through adaptive hypertrophy and
this process is not entirely benign and cannot be continued as overload is
over time; ultimately, the right ventricle dilates and fails. The ability of the
are recognized to underline these changes: nitric oxide (NO), endothelin-1
). As previously explained, NO is a potent pulmonary
2
and it also inhibits platelet aggregation. It is produced by the NO synthe-
in
the production of NO and this causes vasoconstriction, proliferation of
correlates with patients’ survival [32]. PGI
reducing smooth muscle cell proliferation, promoting vasodilatation, and
platelets’ aggregation. PGI2 is antagonized by thromboxane A2 (TXA2),
is a lipid mediator produced
2
increased production of TXA2 and the lacking of PGI2. This causes platelet
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Figure 1.
Pathophysiology of right ventricular failure in PAH. Pulmonary vascular remodeling, the hallmark of PAH, leads
to increase RV afterload and RV wall tension. Initially, the right ventricle can cope with the increased RV
afterload. Homeometric adaptation consists of adaptive hypertrophy and an increase in contractility of the RV as a
response to the rise in RV afterload, with little or no dilatation, hence preserving cardiac output. However, in the
long term, prolonged excessive afterload to the RV, maladaptive RV hypertrophy and ECM changes, inflammation
and myocardial ischemia together lead to failure of the homeometric adaptation and consequently reduced RV
contractility. This increases RV filling pressures and volume (heterometric adaptation) and an attempt to
maintain stroke volume through the Starling principle. There is uncoupling of the RV from the pulmonary. RV
dilatation and uncoupling, together with a significant negative interaction between the RV and LV, lead to a
further increase in RV filling pressure and subsequent drop in cardiac output, precipitating a vicious cycle of events
that lead to heart failure, hypotension, and shock. RV: Right ventricle and ECM: Extracellular matrix.
aggregation, proliferation of smooth muscle cells, vasoconstriction, and an increase in
PVR. Moreover, patients with PAH have reduced production of prostacyclin as well as
reduced expression of prostacyclin receptor and prostacyclin synthase [33].
3.3.3 Clinical picture and prognostic factors of PAH
In the pre-symptomatic stage of PAH, increases in PVR and resting mPAP do not
influence resting cardiac function, such as CO. By the time a patient presents with
symptoms, even with “early” symptoms, (WHO functional class II) PVR is already
significantly above normal, suggesting advanced pulmonary vascular remodeling.
Many clinical symptoms or signs, such as peripheral edema and the onset of angina,
can mark the moment in which the right ventricle function deteriorates. In particular,
patients who begin to experience syncope or who experience an increase in the
frequency of syncopal episodes have poor prognoses and require immediate attention:
syncope has been proved to be an independent risk of poor survival [34]. Less common symptoms, include cough, hemoptysis, and hoarseness.
Patients must be assessed by:
• WHO functional class (FC) describes patients ’ symptoms relating to their
everyday activities and life. WHO-FC is a strong predictor of survival. Patients in
WHO-FC I have no limitation of physical activity; WHO-FC II is characterized
by minor limitation in physical activity; WHO-FC III is characterized by a
manifest limitation of physical activity with no discomfort at rest; finally,
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Соседние файлы в папке Библиотека им академика М.И. Перельмана