Diagnostic Assessment and Confirmation of PAH Learning Objectives Screen high-risk patients for the...

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.