Pah seminar kirti

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