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 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 Dyspnœa may be initial complaint Fatigue Syncope Chest pain PalpitationDeath usually due to RVF
WHO Functional Classification of Pulmonary HypertensionClass I—Patients with PAH but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnœa or fatigue, chest pain, or syncope.Class II—Pt. with PAH resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnœa or fatigue, chest pain, or syncope.
WHO Functional Classification of Pulmonary Hypertension Class III—Pt. with PAH resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnœa or fatigue, chest pain, or syncope. Class IV—Pt with PAH with inability to carry out any physical activity without symptoms. These patients manifest signs of RHF. Dyspnœa 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
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
Factors determining poor prognosis Rapid progression of symptome H/O Syncope Advanced WHO functional class 6 min walking <300 mts Very high & rising BNP levels Pericardial effusion Right atrial pressure <15 mm Hg Decreased C.O
Comparative efficacies of the combination therapy BREATHE 2 study : Epoprostenol + Bosentan more effective compared to Epoprostenol alone. COMBI study: Ilioprost + Bosentan surprisingly caused clinical worsening !!! PACES study: Sildenafil has been found to be more effective than Epoprostenol.
Future Aspects No independent activator of cGMP Inhaled VIP Tyrosine kinase inhibitor Rhokinase inhibitor GENE therapy for BMPR2 Endothelin receptor A antagonist- Ambrisentan
Take Home Message IPAH is a rare disorder Phenotypic expression of many underlying biological abnormality High index of suspicion is required for diagnosis It is a diagnosis of exclusion There is new horizon for future therapy Though prognosis & survival is still unsatisfactory