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Diagnostic Assessment and Confirmation of PAH Learning Objectives • Screen high-risk patients for the hemodynamic and clinical features associated with PAH. • Refer patients for right heart catheterization for diagnostic confirmation. • Follow current guidelines and specifications in order to classify patients with the proper type of pulmonary hypertension. • Use diagnostic tests to assess baseline right ventricular morphology and function. Lecture Outline • Epidemiology • Pathology and genetics • Diagnostic algorithm for PAH • Clinical classification • The right ventricle (RV) in PAH • Screening high-risk patients Epidemiology of PAH • Prevalence in the U.S. ≈ 50,000 to 100,000 – 15,000 to 25,000 diagnosed and treated • Historically: Due to rapid progression of morbidity and mortality, once patients were diagnosed with pulmonary hypertension they were described as entering “the kingdom of the near-dead” • Modern day: Patient survival has dramatically improved as treatment options for PAH have increased McGoon, et al. J Am Coll Cardiol. 2013;62(25):S51-9. The Expansion of Treatment Options for PAH 18 years ago 12 years ago • No treatments for PAH • 1 treatment for PAH Pulmonary Hypertension Association, January 2014. Today • 12 treatment options for PAH Patient Registries for PAH Registry Time Period N NIH 1981 – 1985 187 French 2002 – 2003 674 U.S. Reveal 2006 – 2009 3515 U.S. PHC 1982 – 2006 578 Scottish-SMR 1986 – 2001 374 Chinese 1999 – 2004 72 Spanish 1998 – 2008 866 U.K. 2001 – 2009 482 New Chinese Registry 2008 – 2011 956 Mayo 1995 – 2004 484 Compera 2007 – 2011 587 McGoon, et al. J Am Coll Cardiol. 2013;62(25):S51-9. Observations from Patient Registries for PAH • Older age at diagnosis – NIH registry: 36 (± 15 years) – REVEAL: 50 to 65 (± 15 years) • Population cohorts at greater risk – Patient demographic – advanced age, male gender – Etiology – heritable PAH, PAH associated with connective tissue disease or portal hypertension McGoon, et al. J Am Coll Cardiol. 2013;62(25):S51-9. Patient Registries for PAH: Outcome Predictors High Risk Low Risk Patient demographics Male gender, advanced age Etiology – heritable, associated with CTD or portal hypertension Functional capacity Higher functional class Shorter 6-MWD Lower functional class Longer 6-MWD Laboratory / Biomarkers Higher BNP, NT-proBNP Higher creatinine Lower BNP, NT-proBNP Imaging Echo – pericardial effusion Lung function studies Lower predicted DLCO Higher predicted DLCO Hemodynamics Higher mRAP or PVR Lower CO or CI Higher CO or CI McGoon, et al. J Am Coll Cardiol. 2013;62(25):S51-9. Patient 3-Year Survival Rates: REVEAL Registry P < 0.05 N = 263 Barst, et al. Chest. 2013;144(1):160-8. N = 645 N = 74 Pathology of Pulmonary Hypertension Overview • Pulmonary hypertension (PH) is an obstructive lung panvasculopathy • Patient prognosis is primarily determined by the functional status of the right ventricle (RV) • Most common cause of death is RV failure Tuder, et al. J Am Coll Cardiol. 2013;62(25):S4-12. Pathology of Pulmonary Hypertension Metabolic dysfunction Dysregulation of growth factors Proliferative, apoptosisresistant state Persistent inflammation Tuder, et al. J Am Coll Cardiol. 2013;62(25):S4-12. Disordered mitochondrial structure Interplay of several pathobiological and environmental factors on a “background of genetic predisposition” Pathology of Pulmonary Hypertension Excessive pulmonary vascular remodeling Sustained vasoconstriction In situ thrombosis Increased pulmonary vascular resistance Tuder, et al. J Am Coll Cardiol. 2013;62(25):S4-12. Mechanisms of Pathology for PAH Endothelin pathway Prostacyclin pathway Nitric oxide pathway Endothelial cells Preproendothelin L-arginine Proendothelin Arachidonic acid Prostaglandin I2 NOS Nitric oxide Endothelinreceptor A Endothelin-1 Endothelinreceptor B sGC stimulator Prostaglandin I2 GTP Exogenous nitric oxide cGMP Endothelinreceptor antagonists Phosphodiesterase type 5 Vasodilatation and antiproliferation Vasoconstriction and proliferation Phosphodiesterase type 5 inhibitor Adapted from: Humbert, et al. N Engl J Med. 2004;351:1425-1436. cAMP Prostacyclin derivates Vasodilatation and antiproliferation Genetic Mutations in PAH • BMPR2 – – – – Major predisposing gene Over 300 mutations have been identified Found in >70% of patients with heritable PAH Found in ≈ 20% of patients with idiopathic PAH • ALK-1 – Major gene when PAH is associated with hereditary hemorrhagic telanglectasia (HHT) • Less common mutations: – Endoglin, SMAD9, Caveolin-1, KCNK3 Soubrier, et al. J Am Coll Cardiol. 2013;62(25):S13-21. Genetic Screening and Counseling • Screening recommendations – Subject to debate since it is impossible to determine which carriers of a mutation will develop PAH • Patients with a family history of heritable PAH • Patients with idiopathic PAH, to determine if they are genetic carriers • Counseling – Schedule for routine evaluation / follow-up – Considerations for family planning Soubrier, et al. J Am Coll Cardiol. 2013;62(25):S13-21. Definition of Pulmonary Hypertension • General definition – Mean PAP ≥ 25 mm Hg at rest, measured by right heart catheterization • Hemodynamic characterization of PAH – Mean PAP ≥ 25 mm Hg, PAWP ≤ 15 mm Hg, elevated PVR (> 3 Wood Units) Hoeper, et al. J Am Coll Cardiol. 2013;62(25):S42-50. Diagnostic Algorithm for PAH PAH is a diagnosis of exclusion Hoeper, et al. J Am Coll Cardiol. 2013;62(25):S42-50. Clinical Symptoms Associated with PAH • Suspicion of pulmonary hypertension • Clinical symptoms – Unexplained dyspnea on exertion – Presyncope – Syncope – Signs of right ventricular dysfunction • Other non-specific symptoms in patients with PAH – Fatigue, weakness, angina, abdominal distension, edema Galie, et al. Eur Heart J. 2009;30:2493-2537. Hoeper, et al. J Am Coll Cardiol. 2013;62(25):S42-50. Echocardiography for PAH Doppler ECHO • PAH can not be diagnosed with ECHO • Non-invasive estimation of pulmonary artery pressure (PAP) • Examine ECHO results for: – Left ventricular systolic and diastolic dysfunction – Left-sided chamber enlargement – Valvular heart disease • Examine ECHO with contrast results for: – Intracardiac shunting Badesch, et al. J Am Coll Cardiol. 2009;54:S55-66. Echocardiography for PAH Screening Tools and Tests • Electrocardiogram (ECG) – RV hypertrophy and strain; right atrial dilatation • Chest x-ray • CT scan and pulmonary angiogram – Pulmonary disease; CTEPH – Enlarged pulmonary arteries, • Blood tests and right heart structures • PFT and ABG – Airflow obstruction • V/Q scan – Pulmonary disease; CTEPH Galie, et al. Eur Heart J. 2009;30:2493-2537. Preston. Am J Cardiol. 2013;111(8):S2-9. immunology – Liver disease, CTD, HIV • Abdominal ultrasound – Liver disease, portal hypertension Right Heart Catheterization for PAH • Diagnostic confirmation • Measures: – – – – Pulmonary artery pressure (PAP) Pulmonary artery wedge pressure (PAWP) Cardiac output (CO) Right atrial pressure (RAP) • Allows calculation of resistance – Pulmonary and systemic vascular resistance Badesch, et al. J Am Coll Cardiol. 2009;54:S55-66. Clinical Classification of Pulmonary Hypertension Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41. Clinical Classification of Pulmonary Hypertension Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41. Types of PAH Idiopathic Heritable • BMPR2 • ALK-1, ENG, SMAD9, CAV1, KCNK3 • Unknown Drug- and toxin-induced Associated with: • • • • • Connective tissue disease HIV infection Portal hypertension Congenital heart disease Schistosomiasis Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41. Drug- and Toxin-Induced PAH Definite Likely Possible Unlikely • Aminorex • Fenfluramine • Dexfenfluramine • • • • • Toxic rapeseed oil • Benfluorex • SSRIs Amphetamines L-Tryptophan Methamphetamines Dasatinib • Cocaine • Phenylpropanolamine • St. John’s wort • Oral contraceptives • Estrogen • Cigarette smoking Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41. • Chemotherapeutic agents • Interferon α and β • Amphetamine-like drugs PAH Associated With Connective Tissue Disease • Scleroderma – Most studied type of PAH associated with connective tissue disease – Rate of occurrence of PAH = 7 to 12% of patients with scleroderma – Prognosis is poorer than other types of PAH – 1 year mortality rate = 30% Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41. PAH Associated With HIV Infection • Rate of occurrence of PAH = 0.5% of patients with HIV • Improvement in patient survival rates since the advent of highly-active antiretroviral therapies (HAART) • French registry: 5 year survival rate > 70% Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41. PAH Associated With Portal Hypertension • Rate of occurrence of PAH = 2 to 6% of patients with portal hypertension • Patient prognosis is negatively impacted by: – Severity of liver disease / cirrhosis – Cardiac dysfunction Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41. PAH Associated With Congenital Heart Disease • Greater numbers of children with congenital heart disease survive into adulthood • Rate of occurrence of PAH = 10% of adults with congenital heart disease • The presence of PAH has a profound negative impact on the clinical course for this complex patient group Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41. PAH Associated With Schistosomiasis • Schistosomiasis – Disease caused by parasitic worms (blood flukes) of the genus Schistosoma – Developing countries are the most affected, with more than 200 million people infected worldwide – Of those infected, 10% develop hepatosplenic schistosomiasis • Rate of occurrence of PAH = 5% of patients with hepatosplenic schistosomiasis • 3 year mortality rate ≈ 15% Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41. Type of PAH: REVEAL Registry N = 2967 5.3% 5.3% 1.9% 3.5% 9.8% 46.2% 25.3% 2.7% CTD = connective tissue disease; CHD = congenital heart disease Badesch, et al. Chest. 2010;137(2):376-87. WHO Functional Classification for PAH Class I No limitation of physical activity. Ordinary physical activity does not cause undue dyspnea, fatigue, chest pain, or near syncope. Class II Slight limitation of physical activity; no discomfort at rest. Ordinary activity causes undue dyspnea, fatigue, chest pain, or near syncope. Class III Marked limitation of physical activity; no discomfort at rest. Less than ordinary physical activity causes undue dyspnea, fatigue, chest pain, or near syncope. Class IV Inability to perform any physical activity without symptoms; signs of right ventricular failure or syncope; dyspnea and / or fatigue may be present at rest; discomfort is increased by any physical activity. Taichman, et al. Clin Chest Med. 2007;28:1-22. Anatomy and Physiology of the Ventricles • Right Ventricle (RV) – Thin walled – Crescent shaped – Peristaltic contraction begins at the inflow region and progresses toward the outflow tract (apex to base) – Can adapt to volume overload conditions Rich. Cardiol Clin. 2012;30:257-69. • Left Ventricle (LV) – Greater thickness – Cone / spherical shaped – Contracts in a squeezing, twisting motion from the LV apex to the outflow tract (base) – Can adapt to pressure overload conditions The Role of the Right Ventricle (RV) • Represents a complex interplay between contractility, afterload, compliance, and heart rate • Unlike the left ventricle (LV), the RV is thin walled and distensible; therefore, it is subject to significant size and shape change Vachiery, et al. Eur Resp Rev. 2012;21(123):40-7. RV in Patients with PAH Pulmonary hypertension ↑ PAP (pressure overload) Adaptive RV hypertrophy Progressive contractile impairment RV dilatation Contractile dysfunction progresses RV failure: High RV filling pressures, diastolic dysfunction, ↓ CO Badano, et al. Eur J Echocardiography. 2010;11(1):27-37. RV Remodeling in Patients with PAH • Extent of RV remodeling is influenced by: - Neurohormonal and immunological activation - Coronary perfusion - Myocardial metabolism - Rate and time of onset of pulmonary hypertension - Etiologic cause of PAH - Genetic factors Vonk-Noordegraaf, et al. J Am Coll Cardiol. 2013;62(25):S22-33. RV Remodeling in Patients with PAH Patterns of Ventricular Remodeling • Adaptive remodeling – Concentric remodeling (greater mass-to-volume ratio) – Preserved systolic and diastolic function • Maladaptive remodeling – Eccentric hypertrophy – Poor systolic and diastolic function – Contributes to RV stress Vonk-Noordegraaf, et al. J Am Coll Cardiol. 2013;62(25):S22-33. Continuum of RV Impairment and Action Towards Reversal • When compensatory mechanisms in the RV are exceeded, RV dysfunction develops • Right heart failure manifests clinically as exercise limitation and fluid retention • FDA-approved therapies for PAH reverse RV remodeling – Reduction of afterload – Vasodilation Vonk-Noordegraaf, et al. J Am Coll Cardiol. 2013;62(25):S22-33. Evaluation of RV Function Right Heart Catheterization • Right atrial pressure • Cardiac index • Cardiac output (CO) Echocardiography • • • • Pericardial effusion TAPSE Right atrial area Left ventricular eccentricity • 2D, 3DE volumes / ejection fraction • RV strain • Tei index Vachiery, et al. Eur Resp Rev. 2012;21(123):40-7. Biomarkers • • • • BNP / NT-proBNP Troponin Uric acid Sodium Evaluation of RV Function: Echocardiography • Most common method used in clinical practice to evaluate the RV • Used in patient monitoring to: - Assess the RV - Evaluate RV size and function - Determine cardiac performance impairment - Measure right atrial size - Assess pericardial effusion Agarwal, et al. Am Heart J. 2011;162:201-13. Evaluation of RV Function: Cardiac MRI • Most accurate method for evaluating: – RV mass – RV volume – RV ejection fraction (RVEF) • Possible uses: – Quantify regurgitant volumes, delayed enhancement, myocardial strain, coronary perfusion, and pulmonary pulsatility Vonk-Noordegraaf, et al. J Am Coll Cardiol. 2013;62(25):S22-33. Impact of RV Function on Therapy • RV function can highlight the subtle changes in early disease and prompt rapid initiation of therapy • RV function determines the patient’s functional capacity and survival • Deterioration in RV function mirrors disease progression • Treatment escalation can be guided by RV function correlates Badano, et al. Eur J Echocardiography. 2010;11(1):27-37. Diagnostic Issues • Misdiagnosis1 – Most patients see three or more physicians over a threeyear period before an accurate diagnosis is made • Diagnostic delay1 – Time to reach diagnosis has not improved in 20 years • Advanced disease at diagnosis2 – Approximately 75% of patients have advanced disease at diagnosis (functional class III and IV) 1) Deano, et al. JAMA Intern Med. 2013;173(10):887-93. 2) Thenappan, et al. Eur Respir J. 2007;30(6):1103-10. Diagnostic Delay REVEAL • Interim analysis1 (N = 2967) – Mean duration between symptom onset and diagnostic right heart catheterization = 2.8 years • Cohort study2 (N = 2493) – 21% of patients had symptoms for > 2 years before diagnosis – Delay was more common in younger patients (< 36 years old) and those with a history of respiratory disorders – Clinicians should be suspicious if symptoms are out of proportion to “underlying disease” or they are not responding to treatment 1) Badesch, et al. Chest. 2010;137(2):376-87. 2) Brown, et al. Chest. 2011;140(1):19-26 Screening High-Risk Patients Heritable PAH • Patients with a family history of PAH Drug- and toxin-induced PAH • Patients with a history of high-risk drug / toxin use Associated conditions • Patients with an associated condition: • Connective tissue disease • HIV infection • Portal hypertension • Congenital heart disease • Schistosomiasis Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41. Comorbid Conditions in Patients With PAH Patients (%) N = 2959 Poms, et al. Chest. 2013;144(1):169-76. Summary • Greater number of treatment options for PAH has advanced patient survival. • Right heart catheterization is mandatory for diagnostic confirmation. • Both a delay in diagnosis and misdiagnosis are common and have a catastrophic impact on outcomes. • Screening of high-risk patients is essential. • The continuum of RV impairment in patients should be met with action towards reversal.