This document provides an overview of pulmonary hypertension (PH), including its definition, classification, mechanisms, pathology, clinical presentation, diagnosis, treatment, and prognosis. PH is defined as a mean pulmonary arterial pressure greater than 25 mm Hg at rest. It is classified into 5 groups based on etiology. Common mechanisms include vasoconstriction, vascular obstruction, increased blood flow, and loss of pulmonary vascular bed. Pathology often involves remodeling of small pulmonary arteries and arterioles. Presentation is usually nonspecific symptoms like dyspnea. Diagnosis involves echocardiogram, cardiac catheterization, and ruling out other causes. Treatment includes vasodilators, anticoagulation, diuretics, oxygen supplementation and sometimes

1. Pulmonary Hypertension
DR Doha Rasheedy
Associate professor
Geriatrics and Gerontology Department
ASU
December 2016

2. Definition
• Sustained elevation of a mean pulmonary
arterial pressure greater than 25 mm Hg at rest
or greater than 30 mm Hg during exercise;
• In normal lungs the pulmonary arterial pressure
is about 20/8mmHg and the mean pulmonary
artery pressure is 12–15mmHg.
• It is often characterized by a progressive and
sustained increase in pulmonary vascular
resistance that eventually may lead to right
ventricular (RV) failure.

3. Classification
• Group 1, pulmonary arterial hypertension (PAH)
• Group 2, pulmonary hypertension owing to left-
sided heart disease
• Group 3, pulmonary hypertension owing to lung
diseases and/or hypoxia
• Group 4, chronic thromboembolic pulmonary
hypertension
• Group 5, pulmonary hypertension with unclear or
multifactorial etiologies

6. Mechanisms of pulmonary hypertension
1. pulmonary vasoconstriction due to hypoxia and, to
a lesser extent, to acidosis.
2. vascular obstruction: emboli, pulmonary artery
stenosis
3. increased blood flow (e.g. left-to-right intracardiac
shunts—atrial and ventricular septal defects)
4. loss of pulmonary vascular bed the total cross-
sectional area of the pulmonary vascular bed is
compromised by parenchymal lung disease, with
loss of blood vessels from either a scarring or a
destructive process affecting the alveolar walls. (e.g.
fibrotic lung disease, emphysema).

7. PATHOLOGY
• In many ways the pathologic findings in the
pulmonary vessels of patients with pulmonary
hypertension are similar, regardless of the
underlying cause.
• The most prominent abnormalities are frequently
seen in vessels of the pulmonary arterial tree with
a diameter of less than 1 mm, namely, the small
muscular arteries (0.1–1 mm) and the arterioles
(0.1 mm).

8. Stage1: Narrowing of small vessels:
1. In The muscular arteries show hypertrophy of the
smooth muscle in media layer, and hyperplasia of
the intimal layer lining the vessel lumen.
2. In the arterioles, a significant muscular component
to the vessel wall normally is not present, but with
pulmonary hypertension these vessels undergo
“neomuscularization” of their walls. AND arteriolar
intima proliferates.
• As a result of these changes, the luminal diameter is
significantly decreased, and the pulmonary vascular
resistance is elevated. Ultimately, the lumen may be
completely obliterated and the overall number of
small vessels greatly diminished. the small arterioles
may demonstrate so-called plexiform changes,
appearing as a plexus of small, slitlike vascular
channels.

9. 2- Thickening of the wall of larger (elastic)
pulmonary arteries
• When pulmonary hypertension becomes marked, other
changes are commonly seen in the larger (elastic)
pulmonary arteries (thickening of the wall, particularly in
the media).
3- increased pulmonary vascular resistance
and right ventricular pressure
• As the architectural changes of pulmonary hypertension
progress, both right ventricular and pulmonary arterial
pressures rise because of increased pulmonary vascular
resistance. Cardiac output usually remains normal early in
the course of the process. When the right ventricle fails,
right ventricular end-diastolic pressure rises, and cardiac
output may decrease as well. Right atrial pressure also rises

10. • Pulmonary hypertension is, by definition, an increase
in pressure within the pulmonary circulation. If the
primary component of the vascular change occurs at
the level of the pulmonary arteries or arterioles, as in
the case of cor pulmonale, then pulmonary arterial
pressures (both systolic and diastolic) rise, whereas
the pressure within pulmonary capillaries remains
normal.
• On the other, hand, if pulmonary arterial
hypertension is secondary to pulmonary venous and
pulmonary capillary hypertension (as in the case of
mitral stenosis or left ventricular failure), then
pulmonary capillary pressure is elevated above its
normal level.

11. Idiopathic pulmonary arterial hypertension (IPAH;
formerly called primary pulmonary hypertension)
includes:.
• IPAH usually occurs as a sporadic (i.e., nonfamilial)
disorder, although the disease has a familial basis in
approximately 10% of cases
1. familial pulmonary arterial hypertension.
2. IPAH are observed in conditions associated with
pulmonary arterial hypertension, such as
scleroderma, portal hypertension, and human
immunodeficiency virus (HIV) infection, or with
exposure to drugs and toxins, such as cocaine,
methamphetamine, and certain diet drugs.

12. • Heritable forms of PAH include those with
identified gene mutations and familial cases with
or without mutations:
1. the bone morphogenetic protein receptor type II
(BMPR2)
2. Endoglin
3. Caveolin 1
4. ALK-1 activin like kinase 1
• These abnormalities are believed to lead to
dysregulation of proliferative responses in the
endothelium and pulmonary arterial smooth
muscle cells, producing the well-described
pathologic changes in small pulmonary arteries
and arterioles

13. PAH associated with connective tissue
diseases• Pulmonary hypertension also occurs as a
complication of collagen vascular diseases such as
systemic sclerosis (scleroderma), mixed connective
tissue disease and systemic lupus erythematosus
(SLE).
• These patients have a particularly poor prognosis,
with an estimated 30% 1-year mortality, compared
to 15% in IPAH.
• Cases of reversible PAH have been reported in PAH
patients with systemic lupus erythematosus and
mixed CTD

14. PAH associated with human immunodeficiency
virus.
• prevalence of PAH in this group is estimated to be 0.5%
• Cases of reversible PAH have been reported in HIV
patients treated with PAH drugs and highly-active
antiretroviral drugs
PAH associated with portal hypertension
6% of patients with portal hypertension develop PAH, independent
of the severity of the liver disease,
Portopulmonary hypertension represents an important problem for
liver transplantation programs because its presence is related to
increased mortality during and after the procedure, particularly if
the mPAP is >35 mm Hg.
The prognosis in portopulmonary hypertension is worse than in
IPAH; recently reported data suggest a 3-year survival of 40%

15. Clinical Presentation
• Non specific leading to delayed diagnosis
Symptoms:
• dyspnea (most common), exercise intolerance,
fatigue, substernal chest pain, and palpitations.
• Symptoms of right heart failure include exertional
dizziness, syncope, chest pain, lower extremity
swelling, increased abdominal girth (ascites), and
hoarseness (impingement of recurrent laryngeal
nerve by enlarging pulmonary artery).
• Assess for exposure to anorectic drugs and
symptoms of underlying diseases , family history
of PH

16. • The rise in pulmonary pressure may be acute or
chronic, depending on the causative factors.
• In some cases, chronic pulmonary hypertension is
punctuated by further acute elevations in
pressure, often as a result of exacerbations of the
underlying disease.

17. • Signs: due to cardiac affection in Pulmonary hypertension:
1. an accentuation of the pulmonic component of the second
heart sound (P2) because of earlier and more forceful valve
closure attributable to high pressure in the pulmonary
artery.
2. Murmurs of tricuspid insufficiency are commonly heard,
3. pulmonary insufficiency (Graham-Steell) murmur may be
heard.
4. left parasternal heave due to right ventricular hypertrophy.
5. As the right atrium contracts and empties its contents into
the poorly compliant, hypertrophied right ventricle, a
presystolic gallop (S4) originating from the right ventricle
may be heard.
6. When the right ventricle fails, a mid-diastolic gallop (S3) in
the parasternal region is frequently heard.
7. the jugular veins become distended, and peripheral edema
may develop.

18. DIAGNOSTIC EVALUATION OF THE
PATIENT WITH SUSPECTED PH
Doppler echocardiography: (provisional diagnosis)
• Key findings are right ventricular hypertrophy and
elevated right ventricular systolic pressure. Record
estimated PASP, Estimate volume status, Evaluate
severity of TR.
chest radiography:
• the central (hilar) pulmonary arteries increase in size,
and the vessels often rapidly taper off so that the distal
vasculature appears attenuated.
• hypertrophy of the right ventricle, the cardiac
silhouette may enlarge. This feature is most apparent
on the lateral radiograph, which shows bulging of the
anterior cardiac border

19. Chest radiograph
of patient with
pulmonary
hypertension
attributable to
recurrent
thromboemboli.
Central
pulmonary
arteries are large
bilaterally, but
rapid tapering of
vessels
occurs distally.

21. INVASIVE HEMODYNAMIC TESTING: (Definitive confirmation
by Cardiac catheterization)
• Measurements of right ventricular, pulmonary arterial, and
pulmonary capillary wedge pressures
• assessing the response to acute vasodilator testing to guide
the patient’s subsequent management(A variety of
pulmonary vasodilators can be used to determine who is
most likely to respond to calcium-channel blocker therapy
and also provides prognostic information.
• Positive response to pulmonary vasodilator testing should
include all of the following: 1) decrease in mPAP to <40 mm
Hg; 2) decrease of at least 10 mm Hg in mPAP; and 3)
unchanged or increased cardiac output.
• a lack of acute pulmonary vasodilator response does not
signify a “nonresponder” to PAH therapies.
• Assess for cardiac causes of pulmonary hypertension

22. Perfusion lung scanning:
• is frequently a valuable adjunct in the assessment of patients
with pulmonary hypertension. focal perfusion defects may
suggest chronic organized thromboemboli as a likely cause for
the elevation in pulmonary arterial pressure.
Pulmonary angiography
• may be useful when perfusion scanning is positive in order to
confirm the diagnosis and assess the surgical accessibility of
the obstructing lesions.
pulmonary function tests
• are useful primarily for detecting underlying airflow
obstruction (from chronic obstructive lung disease) or
restricted lung volumes (from interstitial lung disease). As a
result of the pulmonary hypertension itself and loss of the
pulmonary vascular bed, the diffusing capacity may be
decreased and often may be the only other abnormality
noted.

23. Arterial blood gas analysis:
• is highly useful for determining whether
hypoxemia or acidosis plays a role in the
pathogenesis of the pulmonary hypertension

24. THERAPY FOR PAH
• GENERAL MEASURES:
1. Low-level graded aerobic exercise, such as walking, is
recommended. Patients are advised against heavy
physical exertion and isometric exercise, as this may
evoke exertional syncope.
2. Oxygen supplementation to keep saturation above
90% at rest and with exertion, sleep, or altitude is
advisable.
3. A sodium restricted diet is advised and is particularly
important to manage volume status.
4. Routine immunizations, such as those against
influenza and pneumococcal pneumonia, are advised

25. • Specific measures: For IPAH:
1. long-term anticoagulation therapy with warfarin.
The rationale is to decrease in situ thrombosis in
the pulmonary arterial system. Observational
data suggest that anticoagulation may improve
survival in these patients. INR target (1.5 to 2.5).
2. Pulmonary Vasodilators: CALCIUM-CHANNEL
BLOCKERS, PROSTACYCLINS, Nitric oxide
pathway(Phosphodiesterase type 5 inhibitors e.g.
Sildenafil), Endothelin pathway Endothelin
receptor antagonists( bosentan, Ambrisentan)

26. Surgical interventions
• For some patients with debilitating disease and a poor
response to therapy, lung transplantation or combined
heart–lung transplantation is indicated. However, this
form of therapy has very limited availability and does
not offer long-term survival for most patients.
• For CHRONIC THROMBOEMBOLIC DISEASE: surgical
removal of the proximal organized thrombi
(pulmonary thromboendarterectomy) may be a
feasible and highly effective therapeutic option. For
the small vessel or microvascular form of chronic
pulmonary thromboembolism, therapy involves
anticoagulation and agents similar to those used for
IPAH.

27. DRUG THERAPY

28. 1- Calcium-channel blockers
• can be a very effective treatment for those few
patients with an acute response to vasodilator
testing.
• Long-acting nifedipine (epilat retard), diltiazem,
and amlodipine are the most commonly-used
agents.
• Due to its potential for negative inotropic effects,
verapamil should be avoided.

29. 2- PROSTACYCLINS
• Prostacyclin synthase expression is reduced in endothelial
cells from PAH patients, resulting in inadequate production
of prostaglandin I 2 (i.e., prostacyclin), a vasodilator with
antiproliferative effects.
• Available forms:
1. epoprostenol (continuous IV),
2. Treprostinil (continuous subcutaneous, continuous IV,
intermittent inhaled, and oral)
3. iloprost (intermittent inhaled).
• Positive Effects:
improvements in exercise tolerance, as measured by the
6MWD, hemodynamics, quality of life, and survival.
• Side effects:
jaw pain, flushing, nausea, cough, headache, diarrhea, skin
rash, and musculoskeletal pain, erythema at the site of the
subcutaneous infusion.

30. Endothelin Receptors antagonists
• endothelin-1, is a potent vasoconstrictor and
stimulator of cell proliferation is overexpressed in
patients with IPAH.
• Receptors antagonists:
1. Selective endothelin-A receptors antagonist
(Ambrisentan)
2. Non selective endothelin-A, B receptors
antagonist(Bosentan, Macitentan)

31. Nitric oxide pathway
• Nitric oxide (NO) is a potent vasodilator of the
pulmonary circulation, acting through the increase in
cyclic guanosine monophosphate (cGMP), and cleared
mainly as a result of degradation by PDE-5. Reduction
in the expression of NO synthase has been described
as a mechanism associated with the pathogenesis of
PH.
• Currently, there are 2 therapeutic classes of drugs
interacting in the NO pathway, aiming to increase the
direct action of cGMP:
1. PDE-5 inhibitors, which decrease cGMP degradation.
2. soluble guanylate cyclase stimulators, which increase
cGMP production.

32. 1. Phosphodiesterase type 5 inhibitors. Sildenafil,
tadalafil
The most common side effects of the PDE-5 inhibitors
include headache, flushing, dyspepsia, myalgias, and
epistaxis.
2. Soluble guanylate cyclase stimulators. Riociguat.
The most common adverse events included syncope,
headache, dyspepsia, peripheral edema, and
hypotension. Cases of hemoptysis have also been
reported.
• Concomitant use of riociguat and PDE-5 inhibitors is
contraindicated due to hypotension.

33. Prognosis
CMR cardiac magnetic resonance; CPET cardiopulmonary exercise
testing; NYHA New York Heart Association; RAP right atrial pressure;
RVEF right ventricular ejection fraction; TAPSE tricuspid annular plane
systolic excursion; WHO World Health Organization; 6MWD 6-min

34. FUTURE DIRECTIONS
• Oral selexipag is a pulmonary vasodilator that acts on
the human prostaglandin I2 (IP) receptor.(FDA
approved 2015)
• Imatinib is a receptor tyrosine kinase inhibition could
be an interesting antiproliferative approach in PAH.
• A link between inflammation and PAH pathogenesis is
supported by several clinical and preclinical
observations. Anti-inflammatory therapies have been
explored predominantly in CTD-associated PAH, and
small case series have reported clinical response to
immunosuppression using a combination of
cyclophosphamide with glucocorticoids

35. PULMONARY HYPERTENSION
ASSOCIATED WITH PULMONARY
VENOUS HYPERTENSION

36. • Mitral stenosis and chronic left ventricular failure are
the two disorders most frequently associated with
pulmonary venous, and subsequently pulmonary
arterial hypertension.
• The resulting right ventricular hypertrophy is not
included in the category of corpulmonale because the
underlying problem resulting in pulmonary
hypertension is clearly of cardiac, not pulmonary,
origin.
• Pulmonary venous hypertension results not only from
passive elevation in pulmonary venous pressure (or
postcapillary pulmonary hypertension [PH]), but also
from reactive vasoconstriction and structural
remodeling in the pulmonary arterial vasculature (or
precapillary PH)

37. • Pathology:
1. dilated and tortuous capillaries and small veins
may result from high pressures in the pulmonary
veins and capillaries.
2. Long-standing pulmonary venous hypertension is
associated with extravasation of erythrocytes into
the pulmonary parenchyma, hemosiderin-laden
macrophages, and a fibrotic interstitial response.

38. Radiology
Radiographic evidence of pulmonary venous
hypertension includes the following:
1. Redistribution of the blood flow to upper zones
2. Interstitial and alveolar edema
3. Kerley’s B lines
which are small, horizontal lines extending to the
pleura at both lung bases that reflect thickening of
or fluid in lymphatic vessels in interlobular septa, a
consequence of interstitial edema

41. • Treatment of these disorders revolves around
attempts to optimize therapy for the cardiac
disease or at least to decrease pulmonary
venous and capillary pressures. The potential
reversibility of pulmonary arterial
hypertension depends on the chronicity of the
disease and the degree to which the venous
hypertension can be alleviated.

42. References:
1. Vallerie V. McLaughlin, Sanjiv J. Shah, Rogerio Souza, Marc Humbert, Management
of Pulmonary Arterial Hypertension. JACC, 2015(65); 18: 1976 –1997.