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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
Pulmonary Hypertension Association, January 2014.
18 years ago• No treatments
for PAH
12 years ago• 1 treatment for
PAH
Today• 12 treatment
options for PAH
Patient Registries for PAHRegistry 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 fromPatient 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 demographicsMale gender, advanced ageEtiology – heritable, associated with CTD or portal hypertension
Functional capacityHigher functional classShorter 6-MWD
Lower functional classLonger 6-MWD
Laboratory / BiomarkersHigher BNP, NT-proBNPHigher creatinine
Lower BNP, NT-proBNP
Imaging Echo – pericardial effusion
Lung function studies Lower predicted DLCO Higher predicted DLCO
HemodynamicsHigher mRAP or PVRLower 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
Barst, et al. Chest. 2013;144(1):160-8.
N = 263 N = 74N = 645
P < 0.05
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
Tuder, et al. J Am Coll Cardiol. 2013;62(25):S4-12.
Proliferative, apoptosis-resistant
state
Metabolic dysfunction
Disordered mitochondrial
structure
Persistent inflammation
Dysregulation of growth
factors
Interplay of several pathobiological and environmental factors on a
“background of genetic predisposition”
Pathology of Pulmonary Hypertension
Tuder, et al. J Am Coll Cardiol. 2013;62(25):S4-12.
Increased pulmonary vascular
resistance
Sustained vasoconstriction
Excessive pulmonary vascular
remodeling
In situ thrombosis
Mechanisms of Pathology for PAH
Adapted from: Humbert, et al. N Engl J Med. 2004;351:1425-1436.
Nitric oxide
cGMP
Vasodilatation and antiproliferation
Endothelial cells
Nitric oxide pathway
Preproendothelin ProendothelinL-arginine
NOS
Arachidonic acid Prostaglandin I2
Prostaglandin I2
cAMPVasodilatation and
antiproliferationVasoconstriction and
proliferation
Endothelin-receptor A Endothelin-
receptor B
Endothelin pathway Prostacyclin pathway
Endothelin-1
Endothelin-receptor
antagonists
Exogenous nitric oxide
Prostacyclinderivates
Phosphodiesterase type 5 inhibitor
Phosphodiesterase type 5
GTPsGC stimulator
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
Hoeper, et al. J Am Coll Cardiol. 2013;62(25):S42-50.
PAH is a diagnosis of
exclusion
Clinical SymptomsAssociated 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, edemaGalie, 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
– Enlarged pulmonary arteries, right heart structures
• PFT and ABG– Airflow obstruction
• V/Q scan– Pulmonary disease; CTEPH
• CT scan and pulmonary angiogram– Pulmonary disease;
CTEPH
• Blood tests and immunology– Liver disease, CTD, HIV
• Abdominal ultrasound– Liver disease, portal
hypertensionGalie, et al. Eur Heart J. 2009;30:2493-2537. Preston. Am J Cardiol. 2013;111(8):S2-9.
Right Heart Catheterization for PAH
Badesch, et al. J Am Coll Cardiol. 2009;54:S55-66.
• 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
Clinical Classification ofPulmonary Hypertension
Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41.
Clinical Classification ofPulmonary Hypertension
Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41.
Types of PAH
Idiopathic
• BMPR2• ALK-1, ENG, SMAD9, CAV1, KCNK3• Unknown
Heritable
Drug- and toxin-induced
• Connective tissue disease• HIV infection• Portal hypertension• Congenital heart disease• Schistosomiasis
Associated with:
Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41.
Drug- and Toxin-Induced PAH
Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41.
Definite• Aminorex • Toxic rapeseed oil• Fenfluramine • Benfluorex• Dexfenfluramine • SSRIs
Likely
• Amphetamines• L-Tryptophan• Methamphetamines• Dasatinib
Possible• Cocaine • Chemotherapeutic agents• Phenylpropanolamine • Interferon α and β• St. John’s wort • Amphetamine-like drugs
Unlikely• Oral contraceptives• Estrogen• Cigarette smoking
PAH Associated WithConnective 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 WithHIV 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 WithPortal 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 WithCongenital 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 WithSchistosomiasis
• 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
CTD = connective tissue disease; CHD = congenital heart diseaseBadesch, et al. Chest. 2010;137(2):376-87.
N = 2967
46.2%
25.3%
2.7%
9.8%
5.3%5.3% 1.9% 3.5%
WHO FunctionalClassification 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 IIIMarked limitation of physical activity; no discomfort at rest. Less than ordinary physical activity causes undue dyspnea, fatigue, chest pain, or near syncope.
Class IVInability 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
• 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
Rich. Cardiol Clin. 2012;30:257-69.
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
Badano, et al. Eur J Echocardiography. 2010;11(1):27-37.
RV failure:
High RV filling pressures, diastolic dysfunction, ↓ CO
Contractile dysfunction progresses
RV dilatation
Progressive contractile impairment
Adaptive RV hypertrophy
Pulmonary hypertension ↑ PAP (pressure overload)
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
Vachiery, et al. Eur Resp Rev. 2012;21(123):40-7.
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
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 three-year 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 DelayREVEAL
• 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
treatment1) Badesch, et al. Chest. 2010;137(2):376-87. 2) Brown, et al. Chest. 2011;140(1):19-26
Screening High-Risk Patients
• Patients with a family history of PAH
Heritable PAH
• Patients with a history of high-risk drug / toxin use
Drug- and toxin-induced PAH
• Patients with an associated condition:• Connective tissue disease• HIV infection• Portal hypertension• Congenital heart disease• Schistosomiasis
Associated conditions
Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41.
Comorbid Conditionsin Patients With PAH
Poms, et al. Chest. 2013;144(1):169-76.
N = 2959
Pat
ient
s (%
)
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.