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Pulmonary vascular lesionsDr. Kirti Jangra
Dr. Saurabh MittalModerator -Dr. Sudheer Arava
Overview• Anatomy • Pulmonary vascular lesions • Pulmonary hypertension• Histological classification
Pulmonary vasculature
Bronchopulmonary segment
Pulmonary vasculature
• Elastic pulmonary arteries, 500microm• Muscular pulmonary arteries, 80-500microm• Pulmonary arterioles, <80microm• Capillaries, 7-10microm• Adult elastic fibers less compact, irregular,
fragmented
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
Right pulmonary artery
Left pulmonary artery
Pulmonary artery
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
Bronchial artery
Muscular Pulmonary artery
H&E Elastin stain
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
Pulmonary arteriole
Corner vessels
• Arterioles and venules• Where alveolar septa converge• Inspiration - capillaries collapse - corner vessels stretch• Reservoir during inspiration• Single elastic lamina
Pulmonary capillaries
• Gaseous exchange• Produce ACE• Deactivate serotonin, adenosine• Synthesize fibronectin, heparin sulfate, IL-1,
TPA, endothelin1• Endothelial cells have high adhesion
molecules
Pulmonary vein
Pulmonary vascular lesions
• Cellular composition of pulmonary vascular
walls, if abnormal, is described as pulmonary
vascular ‘lesions’
• Pulmonary hypertension
• Vasculitis
Pulmonary Hypertension
Sustained MPAP at rest>25mmHgDisproportionate rise on exercise
(normal MPAP 10mmHg)
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
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
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
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
Clinical Classification Of Pulmonary Hypertension(Dana Point 2008)
J Am Coll Cardiol 2009;54:S43–S54
Updated classification of PH- NICE 2013
JACC Vol. 62, No. 25, Suppl D, 2013
Clinical features
• Dysponea on exertion• Fatigue • Palpitations• Chest Pain• Signs of Right heart Failure: Elevated JVP Hepatomegaly Pedal Edema• Cyanosis• Syncope
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
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
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
Chest Radiograph
1.Prominent pulmonary artery
2.Peripheral Hypovascularity
3.Right Ventricular Enlargement
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
Pulmonary Function Test
• Differentiates between Obstructive and Restrictive Lung Disease
• Assessing diffusion capacity
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
RV, RA Enlargement on Echocardiogram
LV
RA LA
Normal PH
RV
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
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.
PAA
Enlarged main PA on CT Standard view Coronal view
CT SCAN
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.
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
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
Right heart catheterization
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
Management strategy
PAH
General
Supportive
Targetted
Septostomy/ transplantMultidisciplinary approach
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
Supportive therapy Anti-coagulation with warfarin
Diuretics – useful for decongestion
Digoxin
Supplemental oxygen therapy
Exercise training
Advanced therapy
Drugs
ERAs
ProstanoidsPDE-5i
Current and emerging therapies for PAH
Clin Chest Med 34 (2013) 867–880
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
Phosphodiesterase-5 inhibitors
Sildenafil
Tadalafil
Vardenafil
Epoprostenol
Treprostinil
Iloprost
Beraprost
Route
Prostanoids
IV
SC and IV
IV and inhaled
Oral
Agent
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
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%
Prognosis
• Median survival of Idiopathic PAH- 2.8 yearsYEAR SURVIVAL RATES
1 68%
3 48%
5 34%
Survival in terms of EtiologyCHD>IPAH>CTD>HIV
Chest. 2004;126:78S–92S
Gross changes
Intima
• Eccentric intima thickening (smoker, proximal to plexiform)
• Fibrotic (late, CREST, IPAH)• Plexiform• Concentric(onion skin)• Dilation/angiomatoid lesions(distal to
plexiform)
Plexiform lesion
• Characteristic but not pathognomic
• Branching pointes of muscular arteries
• Network of vascular channels
• Endothelial cells
• Concentric laminar thickening
Plexiform lesion
• Severe PH, including IPAH
• PH associated with HIV infection
• Liver cirrhosis
• CREST
• Congenital heart malformations
• Schistosomiasis
Increased expression
• VEGF
• Endothelin-1
• Survivin
Decreased expression
• NO synthase
• Prostacyclin synthase• Caveolin-1
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
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
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
Adventitia
• Biological processing center• Injury sensing tissue• Seat of vascular progenitor cells• sense alterations in their redox status
Cell Smooth muscle cells EC Matrix Endothelial cellsLesion Eccentric Concentri
cFibrotic Plexiform Concentri
cDilation/angiomat
oidNormal
PAPYes No No No No No
Mild/Moderate
PH
Yes No Yes No No No
Severe PH Yes Yes Yes Yes Yes Yes
Table 1Intima Remodeling.
Pathology of Pulmonary HypertensionClin Chest Med. 2007 Mar; 28
Cell Smooth muscle cells EC MatrixNormal PAP Yes* No
Mild/Moderate PH Yes YesSevere PH Yes Yes
Table 2Medial Remodeling.
Pathology of Pulmonary HypertensionClin Chest Med. 2007 Mar; 28
Histological classification
Plexogenic arteriopathy
• Earlier plexiform arteriopathy• Female > male• Endothelial cell proliferation• Factor VIII, CD31• MIB-1 index high
Thrombotic arteriopathy and chronicthromboembolic 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%)
Risk factors CTEPH
• Younger age• H/O previous pulm embolism• Pulm emboli U/K source• APLA• IBD• Osteomyelitis• Hypercoagulable state• FVL mutation
Carcinomatous pulmonary emboli
H&E CD31
Hypoxic arteriopathy
• High altitudes
• Pulmonary circulation responds to a low
oxygen tension with vasoconstriction
• Chronic mountain sickness(Monge disease),
i.e. polycythemia and hyperviscosity
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
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
• 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
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
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
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