histopathological and clinical aspects of pulmonary hypertension

1. Pulmonary vascular lesions
Dr. Kirti Jangra
Dr. Saurabh Mittal
Moderator -Dr. Sudheer Arava

2. Overview
• Anatomy
• Pulmonary vascular lesions
• Pulmonary hypertension
• Histological classification

3. Pulmonary vasculature

5. Bronchopulmonary segment

7. Pulmonary vasculature
• Elastic pulmonary arteries, 500microm
• Muscular pulmonary arteries, 80-500microm
• Pulmonary arterioles, <80microm
• Capillaries, 7-10microm
• Adult elastic fibers less compact, irregular,
fragmented

8. Branching of pulmonary artery
• Conventional branches
-oblique angle, coincident airway
• Supernumerary branches
- 90*angle, unaccompanied
-increase as the arterial tree branches
-’V’ shaped baffle at origin
- more sensitive to 5-HT

9. Right pulmonary artery

10. Left pulmonary artery

11. Pulmonary artery

13. Bronchial artery
• Muscular arteries
• Thick wall reflect the high blood pressure of
the aorta and intercostal arteries
• Double elastic lamina, outer indistinct
• Ends at the level of respiratory bronchioles
• Anastomose with the branches of
the pulmonary arteries

14. Bronchial artery

15. Muscular Pulmonary artery
H&E Elastin stain

16. Classification of pulmonary arterioles
• Pre-acinar/intra-acinar
• Extra-alveolar/within alveolar compartment
• Pre-capillary/post-capillary
• Intra-acinar vessels are associated with
respiratory bronchioles, alveolar ducts and
alveolar walls
• Extra-alveolar vessels are tethered to lung
parenchyma

17. Pulmonary arteriole

18. Corner vessels
• Arterioles and venules
• Where alveolar septa converge
• Inspiration
- capillaries collapse
- corner vessels stretch
• Reservoir during inspiration
• Single elastic lamina

19. Pulmonary capillaries
• Gaseous exchange
• Produce ACE
• Deactivate serotonin, adenosine
• Synthesize fibronectin, heparin sulfate, IL-1,
TPA, endothelin1
• Endothelial cells have high adhesion
molecules

20. Pulmonary vein

21. Pulmonary vascular lesions
• Cellular composition of pulmonary vascular
walls, if abnormal, is described as pulmonary
vascular ‘lesions’
• Pulmonary hypertension
• Vasculitis

22. Pulmonary Hypertension
Sustained MPAP at rest>25mmHg
Disproportionate rise on exercise
(normal MPAP 10mmHg)

24. Burden of disease
 Primary PAH Prevalence- 15-30 cases per million
 Mean age of diagnosis 36 years -Mostly young women (F:M
ratio:2-9:1)
 Secondary to other diseases : varies
– 6-60% in Scleroderma
– 20% in RA
– 30-70% in COAD
– 20-40% in sickle cell disease
 Lack of systematic studies in India
Am J Respir Crit Care Med. 2006;173:1023–30

25. Pulmonary Circulation
• Normal Pulmonary arterial pressure:24/9
mmHg
• Mean Pulmonary arterial presure:15
mmHg
• Distensible low pressure system
• Pulmonary vascular resistance 1/10th of
systemic vascular resistance

26. Old definition
• Pulmonary arterial hypertension (PAH) was defined by
-Mean PAP >25 mmHg at rest or >30 mmHg
with exercise
-PAWP ≤15 mmHg and
-PVR >3 mm Hg/L/min (Wood units)
ESC guidelines. Galie N et al. European Heart Journal (2004) 25, 2243–2278

27. New Definition
• Pulmonary hypertension (PH) is defined as a resting
mPAP≥25 mmHg at right heart catheterization (RHC)
• PAH is defined as a subgroup of PH with:
-PAWP ≤15 mmHg (Pre‐capillary PH)
-Normal or reduced cardiac output
-Absence of other causes of pre‐capillary PH
(PH due to lung diseases, CTEPH, or other rare
diseases)
Badesch et al. J Am Coll Cardiol 2009;54:S55–66

29. Clinical Classification Of Pulmonary
Hypertension(Dana Point 2008)
J Am Coll Cardiol 2009;54:S43–S54

30. Updated classification of PH- NICE 2013
JACC Vol. 62, No. 25, Suppl D, 2013

31. Clinical features
• Dysponea on exertion
• Fatigue
• Palpitations
• Chest Pain
• Signs of Right heart Failure: Elevated JVP
Hepatomegaly
Pedal Edema
• Cyanosis
• Syncope

32. Clinical signs
• Left parasternal lift
• Loud P2
• Right Ventricular S4
• Raised jugular a and v waves
• Hepatojuglar reflex
• Pulsatile Liver
• Holosystolic murmur increasing with inspiration
• Early diastolic murmur (Graham Steel Murmur)
• Early systolic click
• Ejection systolic murmur
• Narrow splitting of 2nd heart sound

33. WHO FC Symptomatic profile
Class I Patients with pulmonary hypertension but without resulting limitation of
physical activity. Ordinary physical activity does not cause dyspnoea or
fatigue, chest pain or near syncope
Class II Patients with pulmonary hypertension resulting in slight limitation of
physical activity. They are comfortable at rest. Ordinary physical activity
causes undue dyspnoea or fatigue, chest pain or near syncope
Class III Patients with pulmonary hypertension resulting in marked limitation of
physical activity. They are comfortable at rest. Less than ordinary activity
causes undue dyspnoea or fatigue, chest pain or near syncope
Class IV Patients with pulmonary hypertension with inability to carry out any
physical activity without symptoms. These patients manifest signs of right
heart failure. Dyspnoea and/or fatigue may even be present at rest
WHO Functional Class
Barst RJ et al. J Am Coll Cardiol 2004

34. Investigations
• Chest Radiograph
• Electrocardiogram
• Arterial blood gas
• PFT
• Connective Tissue Disease Work Up
• HIV Testing
• Polysomnography & Overnight oximetry
• Echocardiography
• Ventilation Perfusion Scan
• Right Heart Catheterisation
• CT & MRI Chest

35. Chest Radiograph
1.Prominent pulmonary artery
2.Peripheral Hypovascularity
3.Right Ventricular Enlargement

36. Electrocardiogram
– Right ventricular hypertrophy or strain
– Chronic right ventricular overload:
• Right axis deviation
• R wave/S wave ratio greater than one in lead V1
• Incomplete or complete RBBB
• Increased P wave amplitude in lead II (P pulmonale) due to right atrial enlargement

37. Pulmonary Function Test
• Differentiates between Obstructive and
Restrictive Lung Disease
• Assessing diffusion capacity

38. Echocardiography
• Transthoracic echocardiography provides several variables which
correlate with right heart haemodynamics including PAP, and
should always be performed in the case of suspected PAH.
• TR Pressure Gradient Difference between Right
Ventricular Pressure and Right Atrial Pressure

39. RV, RA Enlargement on Echocardiogram
LV
RA
LA
Normal PH
RV

40. Estimation Of Systolic PAP By Echo
• Simplified Bernoulli Equation
Peak Tricuspid Regurgitation Pressure Gradient=
4 x (tricuspid regurgitation velocity)²
• PA systolic pressure =Tricuspid regurgitation pressure
gradient +Estimated right atrial pressure
• Right Atrial Pressure :
 Estimation based on the diameter and respiratory variation
of the inferior venacava
 Fixed value of 5 or 10 mmHg is taken.
EXAMPLE,
TRV=3m/s,Calculated TRPG»4x(3)²=36 mmHg
PASP=36 + 5 (Right Atrial Pressure)=41 mmHg

41. Estimation Of Mean PAP
• Mean PAP=0.61 PA systolic pressure + 2 mmHg
EXAMPLE,PASP=41 mmHg(TRV=3m/s)
Mean PAP=0.61x41 +2=27 mmHg
• This could allow the use of Doppler measurements for
approximate estimation of pulmonary arterial pressure.

42. PAA
Enlarged main PA on CT
Standard view Coronal view
CT SCAN

43. Cardiac MRI
• Emerging Modality
• Provides Direct Evaluation
1.RV size, morphology, and function
2.Allows non-invasive assessment of blood flow including
stroke volume.
3.Distensibility of PA
4.Cardiac Output
J Am Coll Cardiol 2008;51:750–757.

44. Serologic Testing
• Selective testing of blood samples is appropriate in known or
suspected PAH
• 40% of patients with IPAH have increased ANA
• Anticentromere antibodies are typically positive in lcSSc as are
positive ANA including U3-RNP, B23, Th/To, and U1-RNP while
in dcSSc, U3-RNP is usually positive
• Anticardiolipin antibodies have been associated with PAH in SLE
• HIV serology and Thyroid Function
Clin Chest Med 34 (2013) 665–681

45. V/Q scan
• V/Q lung scanning has a higher sensitivity than CT scanning in
detecting CTEPH with a sensitivity of 90%-100% and a specificity of
94%-100 % and is still the diagnostic test of choice for suspected
CTEPH
Clin Chest Med 34 (2013) 665–681

46. Right heart catheterization

47. Right heart catheterization
• Gold standard for diagnosis
• Invasive procedure
• Available in few centres
• Usefulness:
 Confirm the diagnosis of PAH
 Assess severity of haemodynamic impairment
 Test the vasoreactivity of pulmonary circulation

48. Management strategy
PAH
General
Supportive
Targetted
Septostomy
/ transplantMultidisciplinary approach

49. General measures
 Avoid harmful precipitants eg. Smoking, anorexigens
 Vaccination against influenza and pneumococcus
 Management of co-morbid conditions eg. Obesity,
hypothyroidism
 Management of associated depression
 Avoidance of pregnancy

50. Supportive therapy
 Anti-coagulation with warfarin
Diuretics – useful for decongestion
Digoxin
Supplemental oxygen therapy
Exercise training

51. Advanced therapy
Drugs
ERAs
Prostanoids
PDE-5i

52. Current and emerging therapies for
PAH
Clin Chest Med 34 (2013) 867–880

53. Endothelin receptor antagonists
Bosentan
Ambrisentan
Sitaxentan
20:1
100:1
6500:1
ETA/ETB selectivity
Sitaxentan has been withdrawn from market by Pfizer in 2010 due to fatal hepatic
failure

54. Phosphodiesterase-5 inhibitors
Sildenafil
Tadalafil
Vardenafil

55. Epoprostenol
Treprostinil
Iloprost
Beraprost
Route
Prostanoids
IV
SC and IV
IV and inhaled
Oral
Agent

56. Atrial septostomy
 In intractable right-heart failure atrial septostomy
improves functional status and hemodynamics
 Useful when added to medical therapy
 Can be used as bridge to lung transplantation

57. Lung transplant
 Should be considered in PAH patients with advanced
disease refractory to medications
 Currently, in 3.2% of lung transplants the indication is
idiopathic PAH
 The post-transplant 5-year survival rate is about 50%

58. Prognosis
• Median survival of Idiopathic PAH- 2.8
yearsYEAR SURVIVAL RATES
1 68%
3 48%
5 34%
Survival in terms of Etiology
CHD>IPAH>CTD>HIV
Chest. 2004;126:78S–92S

78. Gross changes

79. Intima
• Eccentric intima thickening (smoker, proximal
to plexiform)
• Fibrotic (late, CREST, IPAH)
• Plexiform
• Concentric(onion skin)
• Dilation/angiomatoid lesions(distal to
plexiform)

80. Plexiform lesion
• Characteristic but not pathognomic
• Branching pointes of muscular arteries
• Network of vascular channels
• Endothelial cells
• Concentric laminar thickening

81. Plexiform lesion
• Severe PH, including IPAH
• PH associated with HIV infection
• Liver cirrhosis
• CREST
• Congenital heart malformations
• Schistosomiasis

82. Increased expression
• VEGF
• Endothelin-1
• Survivin
Decreased expression
• NO synthase
• Prostacyclin synthase
• Caveolin-1

84. Media
• Smooth muscle cell hypertrophy
• Muscularized arteries, precapillary vessels
• Normally 10–15% of the outside diameter of
muscularized pulmonary arteries
• PAH it approaches 30–60% of the outside
diameter
• Cigarette smoke with no evidence of PH

85. Media
• Hypertrophy and hyperplasia
• Cell proliferation and inhibition of cell
apoptosis
• BMPR2, decreased activated form of smad 1,
serotonin, increased PDGF receptor (PDGFR)-β
expression, tenascin, MMP-2
• Decreased apoptosis

86. Adventitia
• Fibroblasts
• 15% of the external diameter of pulmonary
arteries larger than 50 μm in diameter
• In IPAH arteries, adventitial thickness 28% of
artery diameter, predominantly due to
collagen deposition
• Vasa vasorum in medium size vessels absent

87. Adventitia
• Biological processing center
• Injury sensing tissue
• Seat of vascular progenitor cells
• sense alterations in their redox status

88. Cell Smooth muscle cells EC Matrix Endothelial cells
Lesion Eccentric Concentri
c
Fibrotic Plexiform Concentri
c
Dilation/a
ngiomatoi
d
Normal
PAP
Yes No No No No No
Mild/Mod
erate PH
Yes No Yes No No No
Severe PH Yes Yes Yes Yes Yes Yes
Table 1
Intima Remodeling.
Pathology of Pulmonary Hypertension
Clin Chest Med. 2007 Mar; 28

89. Cell Smooth muscle cells EC Matrix
Normal PAP Yes
*
No
Mild/Moderate PH Yes Yes
Severe PH Yes Yes
Table 2
Medial Remodeling.
Pathology of Pulmonary Hypertension
Clin Chest Med. 2007 Mar; 28

90. Histological classification

94. Plexogenic arteriopathy
• Earlier plexiform arteriopathy
• Female > male
• Endothelial cell proliferation
• Factor VIII, CD31
• MIB-1 index high

97. Thrombotic arteriopathy and chronic
thromboembolic pulmonary hypertension
(CTEPH)
• Pulmonary hypertension after acute pulmonary
thromboembolism, arising immediately or insidiously within
the first 2 years after the initial thromboembolic event
• Silent recurrent pulmonary thromboembolism(30%)

98. Risk factors CTEPH
• Younger age
• H/O previous pulm embolism
• Pulm emboli U/K source
• APLA
• IBD
• Osteomyelitis
• Hypercoagulable state
• FVL mutation

101. Carcinomatous pulmonary emboli
H&E CD31

102. Hypoxic arteriopathy
• High altitudes
• Pulmonary circulation responds to a low
oxygen tension with vasoconstriction
• Chronic mountain sickness(Monge disease),
i.e. polycythemia and hyperviscosity

105. Congestive vasculopathy
• Chronic elevation of the pulmonary venous blood
pressure results in a distinct set of adaptive
pulmonary vascular changes, termed congestive
pulmonary vasculopathy
• Elevated wedge pressure (> 15 mmHg)
• Arterialization of veins
• Localization in the interlobular septa
• Substantial thickening of the arterial adventitia
• Brown induration of the lung

107. Pulmonary veno-occlusive disease and
pulmonary
capillary hemangiomatosis
• Decreased diffusion capacity out of proportion to a
mild elevation of pulmonary arterial pressure
• Capillary congestion prominent(PCH)
• 5–10% of all PAH initially diagnosed as idiopathic
• Vasodilator drugs, such as prostacyclin, are usually
less effective

108. • PVOD now POV( pulmonary occlusive
venopathy)
• PCH now PM(pulmonary microvasculopathy)
• Rare causes of unexplained pulmonary
hypertension
• Treatment with vasoactive agents C/I and may
even be life-threatening

109. Pulmonary occlusive venopathy
• Extensive and diffuse occlusion of pulmonary
venules and veins of various sizes
• Solid or eccentric with multiple
lumina(recanalization)
• Arterialization of venules
• Calcium-encrusting elastic fibers in the walls
of veins or adjacent alveoli
• d/d chronic passive venous hypertension

110. Pulmonary occlusive venopathy
• Hemosiderin are found within the cytoplasm
of alveolar macrophages and type II
pneumocytes , interstitium
• BAL hemorrhage
• Plexiform lesions and fibrinoid arteritis are not
seen

111. Pulmonary microvasculopathy
• Engorged and prominent capillaries
• Line both sides of the alveolar walls
• Invade pulmonary interstitium, vessels, and, less
commonly, airways
• Microvessels can form glomeroloid tufts or
nodules
• Pulmonary hemosiderosis
• Etiology can be neoplastic, unknown angiogenic
stimuli