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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.