SEMINAR

Pulmonary Hypertension Dr. Vineet Gupta Guide : Dr. P.P. Joshi

DefinationPulmonary hypertension (PH) is a hemodynamic and pathophysiological condition defined as an increase in mean pulmonary arterial pressure (PAP) 25 mm Hg at rest as assessed by right heart catheterisation.Normal pressure is 14-18mmHg at rest. 20-25mmHg on exercise.

Clinical Classification of Pulmonary Hypertension

Idiopathic pulmonary hypertension (IPAH)Epidemiology Annual incidence of about 2-6 cases per million population More common in females fourth to fifth decade of life Familail IPAH accounts for 20% of IPAH

Pathobiology

There occurs vasoconstriction, vascular proliferation, thombosis and inflammation.These occurs due to decreased expression of voltage regulated potasssium channel, mutation in bone morphogenetic protein 2 receptor, increased tisssue factor expression, overactivation of serotonin transporter, transcription factor activation of hypoxia-inducible factor-1 alpha, activation of nuclear factor of activated Tcells.

Pathogenesis of Pulmonary ArterialHypertension

Multiple biologic pathways that can lead to pulm hypertension

PresentationSymptoms:Very insidious onsetDyspnoea.Generalised weakness and tiredness.Recurrent syncope or presyncope, often related to exertion.Chest painPalpitation Lower limb edema

Signs:Right ventricular (parasternal) heave may be visible/palpable.JVP may be elevated with prominent a and v waves.Loud pulmonary component of second heart sound.May be fixed or paradoxical splitting of second heart sound.Murmur of pulmonary regurgitation - Graham Steell murmur.Tricuspid regurgitation murmur - if significant right ventricular hypertrophy and dilatation are present.If significant associated tricuspid regurgitation - enlarged pulsatile liver with exaggerated hepato-jugular reflux.Ascites and peripheral oedema - if there is significant right ventricular failure.Lung fields are usually clear.

WORKUP OF A PATIENT WITH UNEXPLAINED PULMONARY HYPERTENSION

InvestigationsRoutine biochemistry screen including LFTsThyroid function test.Autoimmune screeningECG : Right axis deviation An R wave/S wave ratio greater than one in lead V1 Incomplete or complete right bundle branch block Increased P wave amplitude in lead II (P pulmonale) due to right atrial enlargement

Echocardiography

Tricuspid regurgitationRight atrial and ventricular hypertrophyFlattening of interventricular septum Small Left ventricular dimensionDilated Pulmonary ArteryPericardial effusionPoor prognostic signRight atrial pressure so high it impedes normal drainage from pericardiumusually does not induce tamponade since RV under high-pressure and non-collapsible

Pulmonary function tests.Exercise testing: a six-minute walk is often used to test for aerobic capacity and severity of PH but it lacks specificity.High-resolution CT of the thorax to investigate other possible causes of PH.Ventilation/perfusion scanning to exclude thromboembolic cause of pulmonary arterial occlusion.Pulmonary angiography and/or cardiac catheterisation Lung biopsy may be needed to exclude interstitial lung disease.Polysomnography may be used to exclude obstructive sleep apnoea.

Right Heart Catheterization

RA 12 years of age with body weight >40kgNo dose adjustment required in patients with renal impairmentNo predetermined dose adjustments required for concomitant warfarin administration.

Ambrisentan5 or 10 mg once dailyMuch less risk of transaminase elevation (about 1%), but monthly monitoring still requiredNo dose adjustment of warfarin needed.

PDE-5 inhibitors

SildenafilSafetySide effects: headaches, epistaxis, and hypotension (transient)Sudden hearing lossDrug interaction with nitratesFDA approved dose is 20 mg TIDTadalafil 40mg ODVardenafil 5mg OD

Prostacyclin analoguesEpoprostenol, treprostinil, iloprostBenefits VasodilationPlatelet inhibitionAnti-proliferative effectsInotropic effects

EpoprostenolFirst PAH specific therapy available in the mid 1990sLack of acute vasodilator response does not correlate well with epoprostenol unresponsiveness.Very short half life = 2 minutesDelivered via continuous infusion Cost about $100,000/year

EpoprostenolSide effects: headache, jaw pain, flushing, diarrhea, nausea and vomiting, flu-like symptoms, and anxiety/nervousnessComplex daily preparationIndividualized dosingCatheter complicationsDislodgement/malfunction Catastrophic deteriorationEmbolizationInfection (3% deaths)

Treprostinil (Remodulin)Continuous subcutaneous infusion or IV infusionLonger t1/2 = 4 hoursLess risk of rapid fatal deterioriation if infusion stops

TreprostinilIntravenous treprostinilHemodynamic improvements and 6MWD improvements No site painRisk of catheter related bloodstream infection and embolic phenomenonRecent concerns about increased gram-negative bloodstream infections.

Iloprost Inhaled prostacyclinAdministered 6-9 times daily via special nebulizerReported risk of morning syncope

IloprostImprovements in 6 miniute walk test, functional class and hemodynamics observed

Safety and side effectsPotential for increased hypotensive effectwith antihypertensivesIncreased risk of bleeding, especially withco-administration of anticoagulantsFlushing, increased cough, headache, insomniaNausea, vomiting, flu-like syndromeIncreased liver enzymes

Guanylate cyclase stimulantStimulators of the nitric oxide receptor.Dual mode of action. They increase the sensitivity of sGC to endogenous nitric oxide (NO)Directly stimulate the receptor to mimic the action of NO. Riociguatis an oral sGC stimulant that has reported benefit in patients with inoperable and persistent chronic thromboembolic pulmonary hypertension (CTEPH)

Failure of Medical Therapy: Consider Atrial SeptostomyImproves left-sided fillingDecreased right-sided pressuresMay serve as bridge to transplant

Failure of Medical Therapy: Indications for Lung TransplantNew York Heart Association (NYHA) functional class III or IV Mean right atrial pressure >10 mmHg Mean pulmonary arterial pressure >50 mmHg Failure to improve functionally despite medical therapy Rapidly progressive disease

Following Response to TherapySix minute walk testEchocardiogramRight heart catheterizationBNPFunctional class

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