3 OBJECTIVES Learn to define the disorder Classification and prevalence Pathophysiology and histopathologyPresentationScreening and diagnostic methodsFunctional classificationTreatment approachesPrognosisPAH and pregnancy
4 DEFINITIONS PULMONARY ARTERIAL HYPERTENSION Syndrome resulting from restricted blood flow throughthe pulmonary arterial circulation from vascularproliferation, aberrant remodeling and in situ thrombosisresulting in increased pulmonary vascular resistance andultimately right sided heart failure.Hemodynamic state characterized by- Sustained elevation of mean pulmonary artery pressureto >25mm Hg at rest or >30mm Hg with exercise-Mean PCWP and LVEDP<15mm Hg
5 PULMONARY AND SYSTEMIC CIRCULATION Standard pressures-Mean pulmonary artery pressure, 14mm Hg-PCWP, 8-12 mm Hg-LVEDP, 6-12 mm Hg-Systemic arterial pressure <120/80 mm HgPAH pressures-Mean pulmonary artery pressure > 25mm Hg-PCWP and LVEDP < 15 mm Hg-Systemic arterial pressure < 120/80 mm Hg
6 INCIDENCE/PREVALENCE PAH is rareEstimated prevalence of 3050 cases per millionMost common in young womenMean age of diagnosis 36 yearsThe prevalence in certain at-risk groups is higherHIV-infected patients (0.50%)Sickle cell disease (2040%)Systemic sclerosis (16%)5True prevalence may be higher
7 CLASSIFICATION OLD CLASSIFICATION Primary and Secondary In 1998 it was proposed to classify based on-Disorders in between the ones affecting the arterial part ofpulmonary circulation-Disorders affecting venous part of the circulation-Disorders affecting the circulation by altered respiratory function.
8 CLASSIFICATIONThird World Conference on Pulmonary Hypertension, held in Venice, Italy, in 2003.The major changes noted in these revisions were as follows:(1) Replacement of the term primary PH with-Idiopathic pulmonary arterial hypertension (IPAH)-Familial pulmonary arterial hypertension (FPAH) when supportedby genetic testing,(2) Abandonment of the term secondary PH
9 WHO CLASSIFICATION Group I. Pulmonary arterial hypertension (PAH) Idiopathic (IPAH)Familial (FPAH)Associated with (APAH):Connective tissue diseaseCongenital systemic-to-pulmonary shunts-Eisenmenger’s syndromePortal hypertensionHIV infectionDrugs and toxinsOther (thyroid disorders, glycogen storage disease, Gaucher's disease, hereditaryhaemorrhagic telangiectasia, haemoglobinopathies, myeloproliferative disorders,splenectomyAssociated with significant venous or capillary involvementPulmonary veno-occlusive disease (PVOD)Pulmonary capillary haemangiomatosis (PCH)Persistent pulmonary hypertension of the newborn (PPHN)
10 WHO CLASSIFICATIONGroup II. Pulmonary hypertension associated with left heartdiseasesGroup III. Pulmonary hypertension associated with respiratorydiseases and / or hypoxemia (including COPD)Group IV. Pulmonary hypertension due to chronic thromboticand/or embolic disease-Thromboembolic obstruction of proximal pulmonary arteries-Thromboembolic obstruction of distal pulmonary arteries-Pulmonary embolism (tumor, parasites, foreign material)-Sickle cell diseaseGroup V. Miscellaneous group eg. sarcoidosis, histiocytosis X andlymphangiomatosis
11 WHO GROUP I IPAH (idiopathic pulmonary arterial hypertension - Leading cause almost 40% of the cases- No risk factor, family history or geneticmutation.- More common in women- Mean age 52
12 WHO GROUP I FPAH (Familial pulmonary arterial hypertension) - At least 100 families have been identified world wide- Accounts for >6% of all cases of PAH- Pedigree analysis shows an autosomal dominant inheritance withreduced penetrance ( 10% to 20% of carriers are affected)- Two genes in TGF-B receptor family have been linked to FPAH- BMPR-2 and ALK-1- Mutations in bone morphogenetic protein receptor type 2 (BMPR2) have been detected in approx. 71% of patients with FPAH- Mutations in BMPR2 have been detected in 26% of IPAH cases
13 Only a small percentage of carriers of bone morphogenetic protein receptor type 2 (BMPR2) mutations develop pulmonary arterial hypertension (PAH)Conversely, familial PAH can occur in individuals without detectable BMPR2Therefore, modifier genes and/or environmental insults are likely to be important in the pathogenesis of PAHThe multiple-hit hypothesis postulates that multiple insults, either genetic or environmental, are necessary for the development of PAHFarber H, et al. N Engl J Med. 2004;351:
14 PATHOPHYSIOLOGY Exact cause of PAH remains unknown Endothelial dysfunction occurs early on in the diseaseprocessEndothelial dysfunction results inReduced production of vasodilatorsOver production of vasoconstrictorsEndothelial and smooth muscle cell proliferationRemodelling of the pulmonary vascular bed and increased pulmonary vascular resistance (PVR)Increase in pulmonary vascular resistance (PVR)Leads to right ventricular overloadLeads to right ventricular failure and premature death
15 PATHOPHYSIOLOGY Three pathways are involved: 1. Prostacyclin (prostaglandin)2. Nitric oxide (NO)− Cyclic guanosine monophosphate( GMP)- phosphodiesterase 53. EndothelinPlatelets likely play an important role as pro-coagulants by increasing the platelet release of serotonin, vascular endothelial growth factor, and platelet-derived growth factor.
16 PATHOPHYSIOLOGY Reduced production of vasodilators Prostacyclin potent vasodilatorpotent inhibitor of platelet activationtherapy with synthetic forms of prostacyclin may help to correct this deficiencyNitric oxidepossesses anti-proliferative propertiesvasodilatory effect is mediated by cGMPrapidly degraded by phosphodiesterases
17 PATHOPHYSIOLOGY Increased production of vasoactive compounds Endothelin (ET)elevated levels are seen in PAH patientslevels correlate with disease severitydeleterious effects mediated through ETA and ETB receptors5fibrosishypertrophy and cell proliferationinflammationvasoconstrictionEndothelin receptor antagonists can block these effectsET, nitric oxide and Prostacyclin have been the principal focus of research into treatments for PAH
19 HISTOPATHOLOGYThe main histological features of PAH include medial hypertrophy, intimal thickening, adventitial thickening, plexiform lesions and in-situ thrombosis. The plexifom lesion represents a focal proliferation of endothelial and smooth muscle cells resulting in a complex 3-Dimensional deformation of the vessel and is pathognomonic of PAH.
20 PRESENTATION SYMPTOMS High resistance to blood flow through the lungs causes right heart dysfunction and produces:DyspneaFatigueDizzinessSyncopePeripheral edemaAnginal chest pain, particularly during physical exerciseHemoptysisHoarsenessAnorexiaRUQ discomfortSymptoms are non-specific and are commonly attributed to other conditionsOver time, symptoms become more severe and limit normal daily activities
21 PRESENTATION CLINICAL SIGNS Jugular venous distension Prominent P2 Right ventricle heaveTricuspid insufficiency murmurRight side S3 heart soundHepatomegalyPeripheral edema
22 WHY IT IS A DIAGNOSTIC DILEMMA? Low awareness/not a condition seen every day by general physiciansIt often comes in disguise:Non-specific symptoms that are often mild and common to other conditionsConfusion with other diseases such as asthma, COPD and other cardiovascular disordersNo simple means of excluding PAH
23 STEPWISE APPROACH TO DIAGNOSE Diagnosis requires a series of investigations in a four-stage approach:Clinical suspicion of pulmonary hypertensionSymptoms, screening and incidental findingsDetection of pulmonary hypertensionECG, chest radiograph, Doppler echocardiographyIdentification of other causes of pulmonary HTNPulmonary function test, blood gas samples, HRCTPAH evaluation and classificationFunctional capacity and hemodynamics
24 SCREENING HIGH RISK POPULATION Key to early diagnosis – screening high risk populations:Family members of a patient with familial Pulmonary Arterial Hypertension (FPAH)Patients with systemic sclerosis (SSc)Patients with HIVPatients with portopulmonary hypertension (PoPH)International guidelines recommend annual screening with Doppler echocardiography.1-3Right heart catheterisation still only method for definitive diagnosis
25 TOOLS FOR SCREENING Clinical suspicion History and Physical Doppler echocardiography.
26 SCREENING HIGH RISK POPULATION Results of a disease registry in France:Without screening, the majority of patients were diagnosed in WHO FC III or FC IV, and only 24% of patients were in WHO FC II at diagnosis.
27 This slide shows a chest radiograph of an individual with PAH The chest radiograph is a common tool used in the diagnosis of pulmonary arterial hypertension (PAH)1This slide shows a chest radiograph of an individual with PAHThe blue arrows indicate peripheral pruning of the pulmonary vasculature (posteroanterior view)The red arrow indicates enlargement of the central pulmonary arteries (posteroanterior view)The green arrow indicates reduction in the retrosternal air space (lateral view)McLaughlin VV and McGoon M. Circulation. 2006;114:
34 CLARIFY ETIOLOGY Patients with PAH on echocardiogram H/O EDS, snoring, apneasObtain NPSGArthralgias, arthritis, myalgias, skin lesionsObtain serology for CTDRisk of/ exposure to HIVScreen for CTEPHMany patients will not have h/o VTEVQ scan should be ordered.
36 RIGHT HEART CATHETERISATION-THE GOLD STANDARD RHC should always assessright atrial pressure (RAP)systolic, diastolic and mean pulmonary arterial pressure (PAP)pulmonary capillary wedge pressure (PCWP)cardiac output / indexPVR and systemic vascular resistanceblood pressure and arterial and mixed venous oxygen saturationRHC can assess vaso-reactive responseshown in only 1015% of patientssustained response is shown in less than 7% of patients
38 VASOREACTIVITY Testing is done with right heart catheterization Defined as mean pulmonary artery pressure decrease by at least 10 mm Hg to a level below 40 mm Hg, with no decrease in cardiac output.Agents approved- Epoprostenol IV- Adenosine IV- Nitric oxide inhaled
39 FUNCTIONAL ASSESSMENT WHO functional classification6 minute walk test (6 MWT)- Reliable, validated- Correlates with survival- Common endpoint in therapeutic trials
40 WHO FUNCTIONAL CLASSIFICATION There are four WHO functional classes (WHO FC)WHO FC I being the least severeWHO FC IV being the most advancedDifferent classes reflect the impact on a patient’s life in terms of physical activity and symptoms
41 WHO FUNCTIONAL CLASSIFICATION Patients with pulmonary hypertension but without resulting limitation of physical activity. Ordinary physical activity does not cause dyspnea or fatigue, chest pain or near syncopeClass IIPatients with pulmonary hypertension resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain or near syncopeClass IIIPatients with pulmonary hypertension resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnea or fatigue, chest pain or near syncopeClass IVPatients with pulmonary hypertension with inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnea and/or fatigue may even be present at rest
42 6 MINUTE WALK TESTThe 6-minute walk test (6MWT) is an evaluation of exercise capacity in patients with PAH and is used to determine the functional class and is also a prognostic indicatorThe 6-MWT is a critical endpoint in clinical studies assessing therapeutic optionsThe 6-MWT should be performed under supervision and according to a standardised protocol
43 BIOMARKERS N- TERMINAL Pro BNP Hyponatremia - Neuro hormonally released Vasopressininduced- Strongly associated with RHF and poorprognosis
44 TREATMENT There is currently no cure for PAH Prognosis is influenced by the status of WHO FC when treatment is started – those who start therapy in WHO FC I or II demonstrate a better prognosis than those whose therapy is started in the more severe stages1By recognizing and treating patients as early as possible, disease progression may be delayedWithout treatment, patients in WHO FC II can rapidly deteriorate within 6 months to more advanced PAH as evidenced by progression of symptoms.
45 TREATMENT STRATEGY Prevention Screening of high risk patients Optimize therapy for related diseaseSupportive treatment ( aimed at consequences of PAH)Vascular targeted therapy (aimed at reducing/ reversing vasoconstriction, proliferation)Surgical ( atrial septostomy, lung transplantation)
46 SUPPORTIVEAnticoagulants - warfarin for prevention against in situ thrombosis INR goal is Diuretics – for treatment of right heart failure Oxygen therapy – to maintain oxygen saturation at >90% at all times Pneumococcal and yearly influenza vaccination Digoxin Avoidance of High altitudes Air travel Pregnancy NSAID Tobacco use Heavy exertion Beta blockers Decongestant medications High Sodium diet Appetite suppressants
48 CALCIUM CHANNEL BLOCKERS Never given empiricallyReserved for “responders”-Near normalization (PAP to 40 mm) and normal CO-High dose nifedipine or diltiazem-Only half of responders will have long term benefit-Response monitored and with deteriorationtreatment escalated
49 Survival in patients with IPAH based on acute vasoreactivity and treatment with warfarin. In patients who were not vasoreactive, warfarin was associated with a modest survival advantage versus nonreactive patients who were not on warfarin. (Redrawn from Rich S, Kaufmann RN, Levy PS: The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med 327:76–81, 1992.)
50 COMBINATION THERAPY Maximize therapy while minimize toxicity 8 trials with 1600 patients publishedvarious combinations6MWT as the primary endpoint weeksshowed only modest improvementRecommended for Class III and IV who fail toimprove or class II with deterioration
51 SURGICAL OPTIONS Atrial septostomy -Reduced RVEDP, increased CI, increased exercise capacity atexpense of decreased PaO2-Option in patients unresponsive to max Rx-Bridge to transplantationLung transplantation-Typically bilateral lung transplantation-Heart-lung transplantation in patients with PAH secondary tocongenital heart diseasePulmonary thromboendarterectomy for patients with CTEPH
55 PROGNOSIS 15 % one year mortality on modern therapy Markers of poor outcome-High functional class-Poor performance on 6 MWT-High RA pressure-Significant RV dysfunction-RV failure-Low Cardiac index-Elevated N terminal Pro-BNP-Hyponatremia
56 PAH and PREGNANCY Mortality rate approaches 30% Contraception is strongly recommended in women of child bearing age with PAHMechanical contraception (IUD) or surgical sterilization is recommended
57 SummaryPAH is a complex disease involving vascular proliferation, inflammation & remodelingUnexplained dyspnea should be worked up in a stepwise fashionGood history and physical can give clues towards the diagnosis and etiologyDiagnosis in early stage leads to early treatment and better outcome.Echocardiogram is an internationally recommended screening tool.Right heart catheterization is needed for definitive diagnosisCalcium channel blockers are to not be used empiricallyVascular targeted therapies now available and improve quality of life and mortality.Mortality remains high even with the modern pharmacologic interventionsPregnancy is contraindicated because of high mortality
58 REFRENCES Pulmonary Board review 25th edition www.phaonline.org Murray and nadel’s “Textbook of respiratory medicine” 5th edition.Gilead sciences inc.