This document discusses pulmonary hypertension (PH), including its definition, pathophysiology, causes, signs and symptoms, diagnostic evaluation, and radiographic findings. PH is defined as a mean pulmonary arterial pressure over 25 mmHg at rest as assessed by right heart catheterization. The pathophysiology involves pulmonary vasoconstriction, endothelial dysfunction, vascular remodeling, and an imbalance of various mediators. PH can be caused by left heart disease, lung diseases, chronic thromboembolic disease, or other rare diseases. Common signs include dyspnea, fatigue, edema, and right heart failure. Diagnostic tests include echocardiogram, CT, ventilation/perfusion scan, right heart catheterization. Chest x-ray may show

1. - Dr. Akif A.B

2. Definition
 PH is defined as an increase in mean pulmonary
arterial pressure >25 mmHg at rest as assessed
by right heart catheterization (RHC)
 Normal PAPm at rest is 14±3 mmHg with an
upper limit of normal of approximately 20 mmHg

4.  PH has a multifactorial pathobiology:
 Imbalance in vasoconstriction and vasodilation
 Thrombosis,
 Cell proliferation and
 Remodeling of the walls of the pulmonary
arteries contribute to increased PVR

5.  Pulmonary vasoconstriction has been
regarded as an early component of the PH
process
 Excessive vasoconstriction has been related to
abnormal function or expression of potassium
channels and to endothelial dysfunction
 Endothelial dysfunction is characterized by
impaired production of vasodilators such as nitric
oxide (NO) and prostacyclin, along with
overexpression of vasoconstrictors such as
endothelin-1

6.  Pulmonary vascular remodeling involves the
intima, media, and adventitia of small
pulmonary arteries
 All cell types (endothelial, smooth muscle, and
fibroblastic), as well as inflammatory cells and
platelets, may play a significant role in the
condition

7.  Recent genetic and pathophysiologic studies of PH
have emphasized the relevance of several other
mediators, such as angiopoietins, serotonin, bone
morphogenetic proteins (BMPs), and growth
factors (platelet-derived growth factor [PDGF],
fibroblast growth factor [FGF], epidermal growth factor
[EGF], and the transforming growth factor-beta [TGF-
β] superfamily)
 Abnormal proteolysis of the extracellular matrix,
autoimmunity, and inflammation are also likely to
contribute to the pathobiology of PH, and there is a
growing body of literature on the role of cytokines and
chemokines in pulmonary vascular remodeling

8. Pathophysiology of
pulmonary
hypertension in left
heart disease

9.  The increased pulmonary venous pressure
results in disruption of alveolar-capillary walls
termed alveolar-capillary stress failure, resulting
in capillary leakage and acute alveolar edema

10.  This acute stage is reversible
 However with chronically increased pulmonary
venous pressure there is irreversible
remodeling of the alveolar-capillary
membrane as a compensatory mechanism to
decrease the frequency and severity of potentially
life-threatening pulmonary edema

11.  The remodeling affects
both pulmonary venous
and arterial system with
thickening of the capillary
endothelial and alveolar
epithelial cell basement
membranes and pulmonary
veins
 These changes reduce the
permeability of the alveolar-
capillary membrane to
fluids, and prevent
development of pulmonary

12.  The process also results in muscularization of
the arterioles and neointima formation along
with medial hypertrophy of distal small pulmonary
arteries leading to increased pulmonary vascular
resistance
 With long-standing disease, pulmonary edema
becomes less frequent and the clinical picture is
dominated by development of PH and right heart
failure

13.  The development of pulmonary vascular disease
is variable, with some patients developing severe PH
while others being spared of PH despite similar rises
in PCWP
 While why this happens is unknown, some factors
may be responsible
 The patients with large compliant left atria may be
less prone to development of pulmonary edema and
ultimately less severe PH
 Also development of AF may make them more prone
to develop PH

14. No pulmonary hypertension
(PH)
 Fluid is continuously cleared from the alveolar
surface by the Na+ channels and Na+-glucose
co-transport system passively
 Then the adenosine triphosphate (ATP)
dependent Na+-K+ pumps “drain” fluid through
the interstitium and the vascular bed
 In between the alveolar surface and capillary
there is the extracellular matrix with cellular
attachments composed primarily by collagen
type IV

16. Isolated post-capillary PH
(IpcPH)
 This hemodynamic condition leads to a pathological increase in left atrial
pressure (LAP), pulmonary artery wedge pressure (PAWP) and mean pulmonary
artery pressure (mPAP) with pulmonary vascular resistance (PVR) and
diastolic pressure gradient (DPG) still in the normal range
 The increase in capillary hydrostatic pressure promotes some anatomic breaks in
the endothelium and vascular wall and fluid swelling in the interstitium and in the
alveoli
 In addition, some initial impairment in the alveolar surface continuous fluid
reabsorption (by Na+ Channels) and capillary Na+-K+ pumps may occur
 Overall, these disruptive processes are resembled under the “alveolar capillary
stress failure” definition
 Small arteries exhibit endothelial dysfunction and vasoconstriction but no
defined changes in the composition of small pulmonary arteries are
detectable, the pulmonary veins already show some thickness and trend to
arteriolarization

18. CpcPH
 This hemodynamic stage is characterized by a further mechanical injury
and progressive increase in PVR, DPG and Mpap
 As protection toward the excessive fluid swelling from capillaries, a
progressive thickening and collagen proliferation of the lamina
densa occurs
 This phenomenon protects against fluid swelling but compromise
gas exchange diffusion for lengthening the path between air and red
blood cell
 The alveolar surface continuous fluid reabsorption and capillary Na+-K+
pumps activity become fully impaired
 The venous system becomes fully arteriolarized and the small
arteries exhibit a clear muscularization process and remodeling

21. Pulmonary function
abnormalities
 The gas diffusion across the alveolar capillary
membrane is decreased in HF, the degree of
impairment depending on severity of HF
 Leads to decreased FVC, FEV1 and diffusion
capacity of lung for carbon monoxide (DLCO) and
increase in residual volume
 Structural changes in the alveolar-capillary membrane
decrease diffusion capacity of the lung with resultant
impedance to gas transfer contributing to exercise
intolerance

24.  RV EF predicts exercise tolerance and survival
in advanced HF
 However, RV EF is inversely proportional to
PAP; thus, this result could simply reflect the
impact of increased PAP
 PH has been repeatedly shown to be associated
with decreased exercise capacity and shorter
life expectancy in HF

25. Why is RV function a major
determinant of outcome in
HF?

26.  A main reason is ventricular interdependence,
defined as the forces directly transmitted from
one ventricle to the other through the
myocardium and pericardium
 More recent studies pointed also to the
importance of systolic interaction, by which
contraction of one ventricle supports the
contraction of the other
 It is estimated that 20% to 40% of RV systolic
pressure results from LV contraction and that
4% to 10% of LV systolic pressure results
from RV contraction

27. Pre-capillary and post-capillary
pulmonary hypertension
Pre-capillary Post-capillary
Predominantly in the
pulmonary arterioles and
small pulmonary arteries
Left heart disease

28. Isolated Post-Capillary PH
 The raised PAP is a passive phenomenon
 There is no intrinsic pathology in pulmonary
circulation

29. Combined Post and
Precapillary PH
 Chronic passive elevation of PAP leads to
pathologic changes in the small pulmonary
arteries and arterioles such that the process is no
longer passive
 The raised PAP in such cases has dual cause
 Elevated left sided filling pressures
 Intrinsic pulmonary vascular disease
 Termed combined post-capillary and pre-capillary
PH (Cpc-PH)

30. Pulmonary capillary wedge
pressure (PCWP)
 Used to assess left ventricular filling, represent
left atrial pressure, and assess mitral valve
function
 It is measured by inserting a balloon-tipped, multi-
lumen catheter (Swan-Ganz catheter) into a
central vein and advancing the catheter into a
branch of the pulmonary artery
 The balloon is then inflated, which occludes
the branch of the pulmonary artery and then
provides a pressure reading that is equivalent to
the pressure of the left atrium

32.  In most cases, the PCWP is also an estimate of
left ventricular end-diastolic pressure (LVEDP)
 The normal pulmonary capillary wedge
pressure is between 4 to 12 mmHg
 Elevated levels of PCWP might indicate severe
left ventricular failure or severe mitral
stenosis

33. Clinical Significance of PCWP
 To evaluate and diagnose pulmonary arterial
hypertension (PAH), as patients with group 1 PAH
will have PCWP ≤ 15 mmHg
 PCWP is also useful in differentiating cardiogenic
shock (PCWP > 15 mmHg) from non-cardiogenic
shock (PCWP ≤ 15 mm Hg)
 To evaluate blood volume status to guide fluid
administration during hypotensive shock, where the
PCWP goal should be maintained between 12 to 14
mmHg

34.  In many patients with LHD, PAWP may be
reduced to <15 mmHg with diuretics
 For this reason, the effect of an acute volume
challenge on left heart filling pressures has
been considered
 Limited data suggest that a fluid bolus of 500 ml
appears to be safe and may discriminate patients
with PAH from those with LV diastolic
dysfunction

36.  Pulmonary vascular resistance is the resistance
against blood flow from the pulmonary artery to
the left atrium. It is most commonly modeled
using a modification of Ohm’s law

38. Trans-Pulmonary Gradient
 Defined as the difference between the mean
pulmonary arterial pressure and the left atrial
pressure, which is usually equal to pulmonary
capillary wedge pressure (PCWP)
 When transpulmonary gradient is >12 mm Hg
in left heart disease, it is considered as out of
proportion pulmonary hypertension indicating
pulmonary vascular disease

40. Diastolic pulmonary gradient
 (DPG) is the difference between the pulmonary
artery diastolic pressure and pulmonary capillary
wedge pressure
 Normal DPG is 1-3mmHg
 A DPG value ≥ 7 mm Hg signals the presence of
pulmonary vascular remodeling in patients with
combined pre- and post-capillary pulmonary
hypertension (CPCPH)
 A DPG > 30-40 mm Hg is associated with the
worst prognosis and may warrant an aggressive

46. Idiopathic Pulmonary Arterial
Hypertension
 Formerly referred to as primary pulmonary hypertension
(PPH)
 IPAH is a rare disease of unknown cause
 Most common type of group 1 PAH
 IPAH is a sporadic disease for which there is neither a family
history of PAH nor an identified risk factor
 It has a female preponderance (2 : 1 in the NIH registry, 4 : 1 in
the current-day REVEAL registry)
 Even though the mean age at diagnosis was 37 years in the
NIH registry and approximately 50 years in the more recent
registries, IPAH can affect children and adults into their 70s.

47. Drugs causing Pulmonary
Hypertension

48. Pulmonary Arterial Hypertension
Associated With Connective
Tissue Diseases
 Scleroderma

49. Pulmonary Arterial Hypertension
Associated With Human
Immunodeficiency Virus Infection
 Incidence of PAH is approximately 0.5%
 Independent of the CD4+ cell count or previous
opportunistic infections
 Prevalence of HIV-associated PAH has not
changed with the widespread use of highly active
antiretroviral therapy
 Survival rate was 88% at 1 year and 72% at 3
years with a CD4+ lymphocyte count greater

51.  The symptoms of PH are non-specific and mainly
related to progressive right ventricular (RV)
dysfunction
 Initial symptoms are typically induced by exertion
 They include shortness of breath, fatigue,
weakness, angina and syncope

52.  Abdominal distension and ankle oedema will
develop with progressing RV failure

53. Mechanical complications of
PH
 Haemoptysis related to rupture of hypertrophied
bronchial arteries
 Pulmonary arterial dilatation leading to :
 Hoarseness caused by compression of the left recurrent
laryngeal nerve
 Wheeze caused by large airway compression
 Angina due to myocardial ischaemia caused by
compression of the left main coronary artery
 Significant dilation of the PA may result in its rupture
or dissection, leading to signs and symptoms of
cardiac tamponade

54. Physical Signs
 Left parasternal lift
 Accentuated pulmonary component of the second
heart sound
 RV third heart sound
 Pansystolic murmur of tricuspid regurgitation and a
diastolic murmur of pulmonary regurgitation
 Elevated jugular venous pressure, hepatomegaly,
ascites, peripheral oedema

55. ECG in
Pulmonary
Hypertension

56. ECG
 An electrocardiogram (ECG) may provide
supportive evidence of PH, but a normal ECG
does not exclude the diagnosis
 An abnormal ECG is more likely in severe rather
than mild PH

57.  ECG abnormalities may include :
 P pulmonale
 Right axis deviation
 RV hypertrophy
 RV strain
 Right bundle branch block

58.  ECG Criteria of Right Atrial Enlargement
 Right atrial enlargement produces a peaked P wave
(P pulmonale) with amplitude:
 > 2.5 mm in the inferior leads (II, III and AVF)
 > 1.5 mm in V1 and V2

59. RV Hypertrophy and Strain
Dominant R wave in V1 (> 7 mm tall; R/S ratio > 1)
Dominant S wave in V6 (> 7 mm deep; R/S ratio < 1

61.  RV hypertrophy has insufficient sensitivity (55%)
and specificity (70%) to be a screening tool, RV
strain is more sensitive
 Prolongation of the QRS complex and QTc
suggest severe disease

62. ARRHYTMIAS IN PULMONARY
HYPERTENSION
 Supraventricular arrhythmias may occur in
advanced disease, in particular atrial flutter, but
also atrial fibrillation
 Incidence in 25% of patients after 5 years
 Atrial arrhythmias compromise CO and almost
invariably lead to further clinical deterioration
 Ventricular arrhythmias are rare

64.  In 90% of patients with IPAH the chest radiograph
is abnormal at the time of diagnosis
 Central pulmonary arterial dilatation
 ‘pruning’ (loss) of the peripheral blood vessels
 Right atrium (RA) and RV enlargement may be
seen in more advanced cases

65.  A chest radiograph may assist in differential
diagnosis of PH by showing signs suggesting
lung disease (group 3) or pulmonary venous
congestion due to LHD (group 2)
 Degree of PH in any given patient does not
correlate with the extent of radiographic
abnormalities

66. Criteria for PAH
 Enlarged RDPA
>14mm in females or
>16mm in males
 Peripheral pruning
of pulmonary
vasculature-will lose
more than 50%
diameter as they
branch
 Prominent MPA

67. How to measure main pulmonary artery
If we draw a
tangent line from the apex
of the left
ventricle to the
aortic knob(red line)
and measure along
a perpendicular
to that tangent
line (yellow line)
The distance between the
tangent and the main
pulmonary artery
(between two small green
arrows) falls in a range
between 0 mm (touching
the tangent line) to as
much as 15 mm away
from
the tangent line

69. Prominent MPA
 Main pulmonary artery
projects more than the
tangent
 Causes:
1. Increased pressure
2. Increased flow

70. Criteria for RA
enlargement
 Vertical height of rt atrium > 50% of right heart border -most
specific
 Rt. Atrial border extends >3 intercostal spaces
 Measurement from mid vertical line to max. convexity in rt.
Border>5 cm in adult & >4cm in children
 Right atrium extending >1/3 rd of rt hemithorax horizontally

71. RIGHT ATRIAL ENLARGEMENT

72. RV ENLARGEMENT
 Cardiophrenic angle is acute
 Clockwise rotation of heart causes RV to form the
middle portion of the left heart border

75.  Pulmonary function tests and arterial blood gases
identify the contribution of underlying airway or
parenchymal lung disease
 Patients with PAH have usually mild to moderate
reduction of lung volumes related to disease
severity
 Although diffusion capacity can be normal in PAH,
most patients have decreased lung diffusion
capacity for carbon monoxide (DLCO)
 An abnormal low DLCO, defined as <45% of
predicted, is associated with a poor outcome

76.  The differential diagnosis of a low DLCO in PAH
includes PVOD, PAH associated with
scleroderma and parenchymal lung disease
 Due to alveolar hyperventilation at rest, arterial
oxygen pressure (PaO2) remains normal or is
only slightly lower than normal and arterial
carbon dioxide pressure (PaCO2) is
decreased

77.  The prevalence of nocturnal hypoxaemia and
central sleep apnoeas are high in PAH (70–
80%)
 Overnight oximetry or polysomnography
should be performed where obstructive sleep
apnoea syndrome or hypoventilation are
considered

79.  Two-dimensional and Doppler echocardiography
Echocardiography is used for the diagnosis and
quantification of severity of left heart disease like
left ventricular systolic/diastolic dysfunction and
valvular heart disease
 Features suggestive of PH like right atrial (RA)
enlargement and RV dilatation, hypertrophy or
dysfunction

81.  Doppler echocardiography is used to estimate the
right ventricular systolic pressure (RVSP) from
tricuspid regurgitation velocity jet by adding
estimated RA pressure

82. Dilatation of the right cavities, compression of the left cavities,
presence of a pericardial effusion (arrow)

83.  One of the leading theories as to why patients
develop a pericardial effusion is an inability to
reabsorb subepicardial venous and lymphatic
drainage into the right atrium
 Because the chronically overloaded right atrium is
unable to accommodate this drainage, it results in
the formation of a pericardial effusion.

93. RV Base to Apex Ratio

95.  CMR imaging is accurate and reproducible in the
assessment of RV size, morphology and function
and allows non-invasive assessment of blood
flow, including stroke volume, CO, pulmonary
arterial distensibility and RV mass

96.  Contrast-enhanced and unenhanced MR
angiography have a potential in the study of the
pulmonary vasculature in patients with suspected
CTEPH, particularly in clinical scenarios such as
suspected chronic embolism in pregnant women,
young patients or when iodine-based contrast
media injection is contraindicated

98.  Serological testing is required to detect underlying
CTD, hepatitis and human immunodeficiency virus
(HIV)
 Up to 40% of patients with IPAH have elevated
antinuclear antibodies usually in a low titre (1:80)
 It is important to look for evidence of SSc since this
disease has a relatively high prevalence of PAH
 Limited scleroderma typically has antinuclear
antibodies, including anti-centromere, dsDNA, anti-
Ro, U3-RNP, B23, Th/To and U1-RNP

99.  Diffuse Scleroderma typically associated with a
positive U3-RNP
 Patients with systemic lupus erythematosus may
have anticardiolipin antibodies

100.  Patients with CTEPH should undergo
thrombophilia screening, including
antiphospholipid antibodies, anticardiolipin
antibodies and lupus anticoagulant
 HIV testing is required in PAH
 N-terminal pro-brain natriuretic peptide (NT-
proBNP) may be elevated in patients with PH
and is an independent risk predictor in these
patients

101. V/Q Scan
 A ventilation/perfusion (V/Q) lung scan should
be performed in patients with PH to look for
CTEPH
 The V/Q scan has been the screening method of
choice for CTEPH because of its higher sensitivity
compared with CT pulmonary angiogram (CTPA),
especially in inexperienced centres
 A normal- or low-probability V/Q scan effectively
excludes CTEPH with a sensitivity of 90–100%
and a specificity of 94–100%

102. HRCT and CT-PA
 CT imaging is a widely available tool that can provide
important information on vascular, cardiac, parenchymal
and mediastinal abnormalities
 It may suggest the diagnosis of PH (PA or RV
enlargement), identify a cause of PH such as CTEPH or
lung disease
 CT may raise a suspicion of PH in symptomatic patients or
those examined for unrelated indications by showing an
increased PA diameter (≥29 mm) and
pulmonary:ascending aorta diameter ratio (≥1.0)
 A segmental artery:bronchus ratio .1 : 1 in three or
four lobes has been reported to have high specificity for
PH

103. The pulmonary artery (PA) aorta ratio was obtained by
measuring the widest transverse diameter of the PA (blue)
and the corresponding transverse diameter of aorta (red).

104. Grading of
tricuspid
regurgitation
(A)0=There is no
reflux into IVC
(B)2=reflux into IVC
but not hepatic
veins
(C)3=reflux into IVC
and proximal
hepatic veins and
(D) 4=reflux into IVC
and distal hepatic
veins.

105. Maximum mid-transverse diameters of the RV (right arrow) and LV (left
arrow) cavities were measured in the axial plane at their widest points
between the inner surfaces of the free wall and the interventricular septum.
(B) For assessing the right atrial margin (arrow) on CT, right atrial length was
measured from the centre of tricuspid annulus to the superior right atrial
margin.

108. Pulmonary vasoreactivity
testing
 For identification of patients suitable for high-dose
calcium channel blocker (CCB) treatment
 Recommended only for patients with IPAH, HPAH
or drug-induced PAH
 It should be performed at the time of RHC
 In all other forms of PAH and PH the results can
be misleading and responders are rare

109.  Inhaled nitric oxide (NO) at 10–20 parts per million (ppm) is the
standard of care for vasoreactivity testing
 I.V. epoprostenol,i.v. adenosine or inhaled iloprost can be used as
alternatives
 Only about 10% of patients with IPAH will meet these criteria
 The use of CCBs, O2, phosphodiesterase type 5 inhibitors or other
vasodilators for acute vasoreactivity testing is discouraged
A positive acute response is defined as a reduction of
the mean PAP ≥10 mmHg to reach an absolute value of
mean PAP ≤40 mmHg with an increased or unchanged
CO