Slide 1

Idiopathic pulmonary arterial hypertensionBy- Jayeeta BhowmickJunior Resident & MD studentDept of Medicine, IPGME&R Kolkata

1

DEFINITION & PARAMETER OF PAH Mean Pulmonary Arterial Pressure > 25 mm Hg at REST > 30 mm Hg with ExerciseNormal Left Heart Filling PressureNormal Left Ventricular ED Volume95 18 mL in Biplane 2D Transthor. Pulmonary Artery Occlusive Pressure < 15 mm Hg

2

PAHIDIOPATHIC

3

PAHFor diagnosingIDIOPATHIC PAHExclude all other Causes

4

Pulmonary Arterial HypertensionIdiopathic Pulmonary Art. HTNFamilial Pulmonary Art. HTNAssociated with

Collagen vascular disease Congenital systemic pulmonary shuntsPortal hypertensionHIV infectionDrugs and toxinsOtherA

5

Pulmonary Arterial HypertensionIdiopathic Pulmonary Art. HTNFamilial Pulmonary Art. HTNAssociated with

Collagen vascular disease Congenital systemic pulmonary shuntsPortal hypertensionHIV infectionDrugs and toxinsOtherThyroid disordersGlycogen storage diseaseGaucher diseaseHereditary hemorrhagic telangiectasiaHemoglobinopathiesMyeloproliferative disordersSplenectomyA

6

Pulmonary Arterial HypertensionIdiopathic Pulmonary Art. HTNFamilial Pulmonary Art. HTNAssociated with Associated with significant venous or capillary involvement

Collagen vascular disease Congenital systemic-to-pulmonary shuntsPortal hypertensionHIV infectionDrugs and toxinsOtherPulmonary venoocclusive disease

Pulmonary capillary hemangiomatosis

A

7

Pulmonary Arterial HypertensionIdiopathic Pulmonary Art. HTNFamilial Pulmonary Art. HTNAssociated with Associated with significant venous or capillary involvement Persistent pulmonary hypertension of the newborn

Collagen vascular disease Congenital systemic-to-pulmonary shunts Portal hypertensionHIV infectionDrugs and toxinsOtherA

8

BPulmonary hypertension with left heart diseaseLeft-sided atrial or ventricular heart diseaseLeft-sided valvular heart disease

CPulmonary hypertension associated with lung disease and/or hypoxemia

Chronic obstructive pulmonary diseaseInterstitial lung diseaseSleep-disordered breathing Alveolar hypoventilation disorders Chronic exposure to high altitudeDevelopmental abnormalities Revised Clinical Classification of Pulmonary Hypertension

9

Revised Clinical Classification of Pulmonary HypertensionDPulmonary hypertension caused by chronic thrombotic and/or embolic disease

Thromboembolic obstruction of PROXIMAL pulmonary arteries

Thromboembolic obstruction of DISTAL pulmonary arteries

Nonthrombotic pulmonary embolism (tumor, parasites) EMiscellaneous SarcoidosisHistiocytosis XLymphangiomatosisCompression of pulmonary vessels (adenopathy, tumor, fibrosing mediastinitis) From Simmoneau G, Galie N, Rubin LJ, et al: Clinical classification of pulmonary hypertension. J Am Coll Cardiol 43:5S, 2004. (Revision on the WHO classification.)

10

EPIDEMIOLOGY1-2 cases / million Population

Female : Male = 1.7 : 1

Age range 10 40 yrs (mean 35.4 yrs)

Females predominate after Pubertal age group

(Ref: NIH Study)

11

Predisposing FactorsDysfunctional Endothelium

Apoptosis Resistant Cell Line in Vascular intima

Genetic defect in K+ channel

Plasma Serotonin & activating Mutation in Serotonin receptor

Sporadic Genetic mutation as in Familial PAH cases.

Uncontrolled Smooth muscleproliferationProduction of VasoconstrictorNO

12

(contd.)Predisposing Factors

Dysfunctional Endothelium

13

Predisposing FactorsDysfunctional Endothelium

Apoptosis Resistant Cell Line in Vascular intima

Genetic defect in K+ channel

Plasma Serotonin & activating Mutation in Serotonin receptor

Sporadic Genetic mutation as in Familial PAH cases.

14

Dysfunctional Endothelium

Apoptosis Resistant Cell Line in Vascular intima

Genetic defect in K+ channel

Plasma Serotonin & activating Mutation in Serotonin receptor

Sporadic Genetic mutation as in Familial PAH cases.

Mutation in BMPR-2 (25% cases) Mutation in ALK-1

Autosomal dominant with Incomplete penetrance

(contd.)Predisposing Factors

15

Early PAH is characterized by increased apoptosis in the endothelial layer (PAEC)Late PAH is characterized by suppressed apoptosis and increased proliferation in the intima and mediaPatients in early stages of PAH may benefit more from antiapoptotic approachespatients presenting in late stages will benefit from proapoptotic strategies

16

17

Summary of the Neurohumoral Imbalance

18

Schematic Histopathological lesions

19

NORMAL PULMONARY VESSELIN PULMONARY HYPERTENSIONINTIMAMEDIAADVENTTITIAINTIMAMEDIAADVENTTITIACOMPARATIVE HISTOLOGY

20

Overexpression of Endothelin in Plexiform Lesions of PAH

21

Clinical featuresEarly stage - difficult to recognize

Exertional Dyspna may be initial complaintFatigueSyncopeChest pain Palpitation

Death usually due to RVF

22

WHO Functional Classification of Pulmonary HypertensionClass IPatients with PAH but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspna or fatigue, chest pain, or syncope.

Class IIPt. with PAH resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspna or fatigue, chest pain, or syncope.

23

WHO Functional Classification of Pulmonary Hypertension

Class IIIPt. with PAH resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspna or fatigue, chest pain, or syncope.

Class IVPt with PAH with inability to carry out any physical activity without symptoms. These patients manifest signs of RHF. Dyspna and/or fatigue may even be present at rest. Discomfort is increased by any physical activity.

24

On Examination

Prominent Jugular Venous Pulsation a or v wave High pitched holosystolic murmur of TR

Prominent large a wavesSystolic murmur of TR

25

contd. On Examination

P 2 Loud with split

Left Lower Parasternal impulse

Bipedal Oedema

26

contd. On ExaminationEarly diastolic high pitched Graham-Steell murmur of PRCaused by dilatation of the PV ring due to PAHS3 S4 gallop

27

Investigations

To confirm the presence of PAH

To search for the secondary causes

To assess prognosis & prerequisites for treatment

28

Chest X Ray

29

ECG

30

Echocardiogram

31

CT Scan

Primary pulmonary hypertension in a 32-year-old woman with average systolic pulmonary arterial pressures of 140-150 mm Hg. CT shows enlargement of the central pulmonary arterial system with tapering to the periphery and corkscrew-shaped arteries.

32

Right heart catheterization

For Establishment of Definite diagnosis

33

Investigations to exclude the secondary causesPFT : Obstructive Vs Restrictive Lung disease

Serology: ANA, HIV

LFT and USG Abdomen

Polysomnography / Overnight Oximetry

34

History and Physical examinationECG ; CXRPulmonary Hypertension suspectedPAH unlikelyNonDiagnostic or consistent with PAH ; PAH still suspectedEchocardiographyRight Heart CatheterizationExclude PAHDiagnose PAHEvaluate or treat airway or Parenchymal Lung disease, collagen vascular disease, neuromuscular disease, or chest wall restrictive diseaseLikely cause suggested by History, Physical examination, CXR, PFT, ABG & SerologyYESNOEchocardiography suggests causeEvaluate & treat mitral valve dis, Congenital Ht Dis, LV Dys? Radionuclide studyV/Q scan or Helical CT suggests high probability for PEFurther evaluation of PAH; Open Lung biopsy rarely neededEvaluate for Sleep related breathing disorders & Nocturnal O2 desaturationEvaluate & treat chronic recurrent thromboembolic disease? Pulmonary angioV/Q scan or Helical CT Normal or Low probability for PE, are there clinical indications for Polysomnography?

35

36

37

Treatment GoalTo improve symptoms

To improve exercise capacities

To prevent further functional worsening

To improve survival

38

General MeasuresRest and Exercise Limitation.Digoxin : C.O.Diuretics: Peripheral Edema RVV overload in presence of TRO2 therapyAnticoagulation: Warfarin in Low doses (maintain INR 2-3)

39

Specific Treatment OptionsVasodilators like CCB (for vasoreactive patients) MOA: 1. Decrease intracellular Ca2+ in vascular smooth muscles.2. Growth inhibitory property of vascular smooth muscles. Dosage: High doseAmlodipine 20 - 30 mg dailyNifedipine 180 200 mg dailyDiltiazem 720 960 mg daily

40

Theraputic RespondersFall in mean pulmonary arterial pressure of atleast 10 mm Hg

Fall to an absolute mean PAP 35 -40 mm Hg

Unchanged or increased C.O.

41

ProstacyclinesMOA-potent pulmonary vasodialatorsEpoprostenil-i.v continuous infusionTreprostenil-S.CIllioprost-aerosol deviceBeraprost-oralIncreased short term survivalAntithrombotic effect

42

Phosphodiesterase 5 inhibitorsIncreased cyclic GMP-vasodilatation

Preferential effect on pulmonary circulation

Dose -20 mg tds

43

44

Endothelin receptors & their antagonists

45

Endothelin receptor antagonistsIncreased exercise capacity

Hemodynamic improvement

Dose Bosentan 125 mg BD

Only side effect- mild elevation of Hepatic enzymes

46

Surgical management

Atrial Septostomy

Lung Transplant

47

Factors determining poor prognosisRapid progression of symptome

H/O Syncope

Advanced WHO functional class

6 min walking