DEFINITION & PARAMETER OF PAH Mean Pulmonary Arterial
Pressure > 25 mm Hg at REST > 30 mm Hg with Exercise Normal
Left Heart Filling PressureNormal Left Ventricular ED Volume 95 18
mL in Biplane 2D Transthor. Pulmonary Artery Occlusive Pressure
< 15 mm Hg
PAH IDIOPATHIC
PAH For diagnosing IDIOPATHIC PAH Exclude all other Causes
Revised Clinical Classification of Pulmonary Hypertension
Pulmonary Arterial Hypertension Collagen vascular disease
Idiopathic Pulmonary Art. HTN Congenital systemic pulmonary shunts
Portal hypertension Familial Pulmonary Art. HTN HIV infection
Associated with Drugs and toxins Other
Revised Clinical Classification of Pulmonary Hypertension
Pulmonary Arterial Hypertension Collagen vascular disease
Idiopathic Pulmonary Art. HTN Congenital systemic pulmonary shunts
Portal hypertension Familial Pulmonary Art. HTNThyroid disorders
HIV infectionGlycogen storage diseaseGaucher disease Associated
with Drugs and toxinsHereditary hemorrhagic Other
telangiectasiaHemoglobinopathiesMyeloproliferative
disordersSplenectomy
Revised Clinical Classification of Pulmonary Hypertension
Pulmonary venoocclusive Pulmonary Arterial Hypertension disease
Collagen vascular disease Pulmonary Idiopathic Pulmonary Art. HTN
capillary Congenital systemic-to- pulmonary shunts hemangiomatosis
Portal hypertension Familial Pulmonary Art. HTN HIV infection
Associated with Drugs and toxins Other Associated with significant
venous or capillary involvement
Revised Clinical Classification of Pulmonary Hypertension
Pulmonary Arterial Hypertension Collagen vascular disease
Idiopathic Pulmonary Art. HTN Congenital systemic-to- pulmonary
shunts Portal hypertension Familial Pulmonary Art. HTN HIV
infection Associated with Drugs and toxins Other Associated with
significant venous or capillary involvement Persistent pulmonary
hypertension of the newborn
Revised Clinical Classification of Pulmonary
HypertensionPulmonary hypertension with left heart disease
Left-sided atrial or ventricular heart disease Left-sided valvular
heart diseasePulmonary hypertension associated with lung
diseaseand/or hypoxemia Chronic obstructive pulmonary disease
Interstitial lung disease Sleep-disordered breathing Alveolar
hypoventilation disorders Chronic exposure to high altitude
Developmental abnormalities
Revised Clinical Classification of Pulmonary Hypertension
Pulmonary 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) Miscellaneous
Sarcoidosis Histiocytosis X Lymphangiomatosis Compression of
pulmonary vessels (adenopathy, tumor, fibrosing mediastinitis)From
Simmoneau G, Galie N, Rubin LJ, et al: Clinical classification of
pulmonaryhypertension. J Am Coll Cardiol 43:5S, 2004. (Revision on
the WHO classification.)
EPIDEMIOLOGY 1-2 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)
Predisposing Factors1. Dysfunctional Endothelium2. Apoptosis
Resistant Cell Line in Vascular intima Uncontrolled Production of
NO Smooth muscle Vasoconstrictor proliferation3. Genetic defect in
K+ channel4. Plasma Serotonin & activating Mutation in
Serotonin receptor5. Sporadic Genetic mutation as in Familial PAH
cases.
Predisposing Factors1. Dysfunctional Endothelium2. Apoptosis
Resistant Cell Line in Vascular intima3. Genetic defect in K+
channel4. Plasma Serotonin & activating Mutation in Serotonin
receptor5. Sporadic Genetic mutation as in Familial PAH cases.
(contd.) Predisposing Factors1. Mutation in BMPR-2 (25% cases)
Dysfunctional Endothelium Mutation in ALK-1 Autosomal dominant2.
Apoptosis Resistant Cell Line in Vascular intima3. with +Incomplete
Genetic defect in K channel penetrance4. Plasma Serotonin &
activating Mutation in Serotonin receptor5. Sporadic Genetic
mutation as in Familial PAH cases.
Patients in early stages of PAH may benefit more from
antiapoptotic approaches Early PAH is characterized by increased
apoptosis in the endothelial layer (PAEC)Late PAH is characterized
bysuppressed apoptosis andincreased proliferation inthe intima and
media patients presenting in late stages will benefit from
proapoptotic strategies
Summary of the Neurohumoral Imbalance
Schematic Histopathological lesions
COMPARATIVE HISTOLOGY INTIMAINTIMA MEDIA MEDIA ADVENTTITIA
ADVENTTITIANORMAL PULMONARY VESSEL IN PULMONARY HYPERTENSION
Overexpression of Endothelin in Plexiform Lesions of PAH
Clinical featuresEarly stage - difficult to recognize
Exertional Dyspna may be initial complaint Fatigue Syncope Chest
pain PalpitationDeath usually due to RVF
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.
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.
On ExaminationProminent Jugular Venous Pulsation a or v wave
Systolic murmur of TR Prominent large a waves High pitched
holosystolic murmur of TR
contd. On Examination P 2 Loud with split Left Lower
Parasternal impulse Bipedal Oedema
contd. On ExaminationEarly diastolic high pitched Graham-Steell
murmur ofPRCaused by dilatation of the PV ring due to PAH S3 S4
gallop
Investigations To confirm the presence of PAH To search for the
secondary causes To assess prognosis & prerequisites for
treatment
Chest X Ray
ECG
Echocardiogram
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.
For Establishment of Definite diagnosisRight heart
catheterization
Investigations to exclude the secondary causes PFT :
Obstructive Vs Restrictive Lung disease Serology: ANA, HIV LFT and
USG Abdomen Polysomnography / Overnight Oximetry
History and Physical examination Pulmonary Hypertension
suspected ECG ; CXR NonDiagnostic or consistent with PAH unlikely
PAH ; PAH still suspected Echocardiography Right Heart
Catheterization YES Exclude PAH Diagnose PAH NO Evaluate or treat
airway or Parenchymal Likely cause suggested by History, Lung
disease, collagen vascular disease, Physical examination, CXR, PFT,
neuromuscular disease, or chest wall ABG & Serology restrictive
diseaseEvaluate & treat mitral valve dis, Echocardiography
suggests causeCongenital Ht Dis, LV Dys? Radionuclide study V/Q
scan or Helical CT suggestsEvaluate & treat chronic recurrent
high probability for PEthromboembolic disease? Pulmonary angio
Treatment Goal To improve symptoms To improve exercise
capacities To prevent further functional worsening To improve
survival
General Measures Rest and Exercise Limitation. Digoxin : C.O.
Diuretics: Peripheral Edema RVV overload in presence of TR O2
therapy Anticoagulation: Warfarin in Low doses (maintain INR
2-3)
Specific Treatment Options Vasodilators like CCB (for
vasoreactive patients) MOA: 1. Decrease intracellular Ca2+ in
vascular smooth muscles. 2. Growth inhibitory property of vascular
smooth muscles. Dosage: High dose Amlodipine 20 - 30 mg daily
Nifedipine 180 200 mg daily Diltiazem 720 960 mg daily
Theraputic Responders Fall 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.
Prostacyclines MOA-potent pulmonary vasodialators
Epoprostenil-i.v continuous infusion Treprostenil-S.C
Illioprost-aerosol device Beraprost-oral Increased short term
survival Antithrombotic effect