PULMONARY HYPERTENSION
ADIL K. WARSY M.D.
PGYV PULMONARY FELLOW
FINANCIAL DISCLOSURES
• None
OBJECTIVES
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Learn to define the disorder
Classification and prevalence
Pathophysiology and histopathology
Presentation
Screening and diagnostic methods
Functional classification
Treatment approaches
Prognosis
PAH and pregnancy
DEFINITIONS
• PULMONARY ARTERIAL HYPERTENSION
Syndrome resulting from restricted blood flow through
the pulmonary arterial circulation from vascular
proliferation, aberrant remodeling and in situ thrombosis
resulting in increased pulmonary vascular resistance and
ultimately right sided heart failure.
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Hemodynamic state characterized by
- Sustained elevation of mean pulmonary artery pressure
to >25mm Hg at rest or >30mm Hg with exercise
-Mean PCWP and LVEDP<15mm Hg
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 Hg
• PAH pressures
-Mean pulmonary artery
pressure > 25mm Hg
-PCWP and LVEDP < 15
mm Hg
-Systemic arterial pressure
< 120/80 mm Hg
INCIDENCE/PREVALENCE
• PAH is rare
• Estimated prevalence of 3050 cases per million
• Most common in young women
• Mean age of diagnosis 36 years
• The prevalence in certain at-risk groups is higher
• HIV-infected patients (0.50%)
• Sickle cell disease (2040%)
• Systemic sclerosis (16%)5
• True prevalence may be higher
CLASSIFICATION
• OLD CLASSIFICATION
Primary and Secondary
• In 1998 it was proposed to classify based on
-Disorders in between the ones affecting the arterial part of
pulmonary circulation
-Disorders affecting venous part of the circulation
-Disorders affecting the circulation by altered respiratory function.
CLASSIFICATION
• Third 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 supported
by genetic testing,
(2) Abandonment of the term secondary PH
WHO CLASSIFICATION
• Group I. Pulmonary arterial hypertension (PAH)
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Idiopathic (IPAH)
Familial (FPAH)
Associated with (APAH):
Connective tissue disease
Congenital systemic-to-pulmonary shunts-Eisenmenger’s syndrome
Portal hypertension
HIV infection
Drugs and toxins
Other (thyroid disorders, glycogen storage disease, Gaucher's disease, hereditary
haemorrhagic telangiectasia, haemoglobinopathies, myeloproliferative disorders,
splenectomy
Associated with significant venous or capillary involvement
Pulmonary veno-occlusive disease (PVOD)
Pulmonary capillary haemangiomatosis (PCH)
Persistent pulmonary hypertension of the newborn (PPHN)
WHO CLASSIFICATION
• Group II. Pulmonary hypertension associated with left heart
diseases
• Group III. Pulmonary hypertension associated with respiratory
diseases and / or hypoxemia (including COPD)
• Group IV. Pulmonary hypertension due to chronic thrombotic
and/or embolic disease
-Thromboembolic obstruction of proximal pulmonary arteries
-Thromboembolic obstruction of distal pulmonary arteries
-Pulmonary embolism (tumor, parasites, foreign material)
-Sickle cell disease
• Group V. Miscellaneous group eg. sarcoidosis, histiocytosis X and
lymphangiomatosis
WHO GROUP I
• IPAH (idiopathic pulmonary arterial
hypertension
- Leading cause almost 40% of the cases
- No risk factor, family history or genetic
mutation.
- More common in women
- Mean age 52
WHO GROUP I
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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 with
reduced 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
PATHOPHYSIOLOGY
• Exact cause of PAH remains unknown
• Endothelial dysfunction occurs early on in the disease
process
• Endothelial dysfunction results in
• Reduced production of vasodilators
• Over production of vasoconstrictors
• Endothelial and smooth muscle cell proliferation
• Remodelling of the pulmonary vascular bed and increased
pulmonary vascular resistance (PVR)
• Increase in pulmonary vascular resistance (PVR)
• Leads to right ventricular overload
• Leads to right ventricular failure and premature death
PATHOPHYSIOLOGY
• Three pathways are involved:
1. Prostacyclin (prostaglandin)
2. Nitric oxide (NO)− Cyclic guanosine monophosphate
( GMP)- phosphodiesterase 5
3. Endothelin
• Platelets likely play an important role as pro-coagulants by
increasing the platelet release of serotonin, vascular
endothelial growth factor, and platelet-derived growth
factor.
PATHOPHYSIOLOGY
• Reduced production of vasodilators
• Prostacyclin
• potent vasodilator
• potent inhibitor of platelet activation
• therapy with synthetic forms of prostacyclin may help to
correct this deficiency
• Nitric oxide
• potent vasodilator
• possesses anti-proliferative properties
• vasodilatory effect is mediated by cGMP
• rapidly degraded by phosphodiesterases
PATHOPHYSIOLOGY
• Increased production of vasoactive compounds
• Endothelin (ET)
• elevated levels are seen in PAH patients
• levels correlate with disease severity
• deleterious effects mediated through ETA and ETB receptors5
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fibrosis
hypertrophy and cell proliferation
inflammation
vasoconstriction
• Endothelin receptor antagonists can block these effects
• ET, nitric oxide and Prostacyclin have been the
principal focus of research into treatments for PAH
DISEASE PATHWAY IN PAH
HISTOPATHOLOGY
PRESENTATION
SYMPTOMS
• High resistance to blood flow through the lungs causes
right heart dysfunction and produces:
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Dyspnea
Fatigue
Dizziness
Syncope
Peripheral edema
Anginal chest pain, particularly during physical exercise
Hemoptysis
Hoarseness
Anorexia
RUQ discomfort
• Symptoms are non-specific and are commonly attributed to
other conditions
• Over time, symptoms become more severe and limit normal
daily activities
PRESENTATION
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CLINICAL SIGNS
Jugular venous distension
Prominent P2
Right ventricle heave
Tricuspid insufficiency murmur
Right side S3 heart sound
Hepatomegaly
Peripheral edema
WHY IT IS A DIAGNOSTIC DILEMMA?
• Low awareness/not a condition seen every day by general physicians
• It often comes in disguise:
• Non-specific symptoms that are often mild and common to other conditions
• Confusion with other diseases such as asthma, COPD and other cardiovascular
disorders
• No simple means of excluding PAH
STEPWISE APPROACH TO DIAGNOSE
Diagnosis requires a series of investigations in a four-stage
approach:
• Clinical suspicion of pulmonary hypertension
Symptoms, screening and incidental findings
• Detection of pulmonary hypertension
ECG, chest radiograph, Doppler echocardiography
• Identification of other causes of pulmonary HTN
Pulmonary function test, blood gas samples, HRCT
• PAH evaluation and classification
Functional capacity and hemodynamics
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 HIV
– Patients with portopulmonary hypertension (PoPH)
• International guidelines recommend annual
screening with Doppler echocardiography.
• Right heart catheterisation still only method for
definitive diagnosis
1-3
TOOLS FOR SCREENING
• Clinical suspicion
• History and Physical
• Doppler echocardiography.
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.
ECG
ECHOCARDIOGRAPHY
Specificity moderate : PAP overestimated in patients with advanced lung
disease
NONINVASIVE TESTING
• Full PFTs with DLCO help identify
COPD
Interstitial lung disease
• ABG
• CT scan
Lung pathology
Pulmonary embolism
• HRCT
Interstitial lung disease
CT SCAN
CT SCAN
VQ SCAN in CTEPH
CLARIFY ETIOLOGY
• Patients with PAH on echocardiogram
 H/O EDS, snoring, apneas
Obtain NPSG
 Arthralgias, arthritis, myalgias, skin lesions
Obtain serology for CTD
 Risk of/ exposure to HIV
 Screen for CTEPH
Many patients will not have h/o VTE
VQ scan should be ordered.
RIGHT HEART CATHETERISATION-THE
GOLD STANDARD
RIGHT HEART CATHETERISATION-THE
GOLD STANDARD
• RHC should always assess
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right atrial pressure (RAP)
systolic, diastolic and mean pulmonary arterial pressure (PAP)
pulmonary capillary wedge pressure (PCWP)
cardiac output / index
PVR and systemic vascular resistance
blood pressure and arterial and mixed venous oxygen saturation
• RHC can assess vaso-reactive response
• shown in only 1015% of patients
• sustained response is shown in less than 7% of patients
RIGHT HEART CATHETERISATION-THE
GOLD STANDARD
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
FUNCTIONAL ASSESSMENT
• WHO functional classification
• 6 minute walk test (6 MWT)
- Reliable, validated
- Correlates with survival
- Common endpoint in therapeutic trials
WHO FUNCTIONAL CLASSIFICATION
• There are four WHO functional classes (WHO FC)
• WHO FC I being the least severe
• WHO FC IV being the most advanced
Different classes reflect the impact on a patient’s life in
terms of physical activity and symptoms
WHO FUNCTIONAL CLASSIFICATION
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Class I
Patients with pulmonary hypertension but without resulting limitation of
physical activity. Ordinary physical activity does not cause dyspnea or fatigue,
chest pain or near syncope
Class II
Patients 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 syncope
Class III
Patients 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 syncope
Class IV
Patients 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
6 MINUTE WALK TEST
• The 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 indicator
• The 6-MWT is a critical endpoint in clinical studies
assessing therapeutic options
• The 6-MWT should be performed under
supervision and according to a standardised
protocol
BIOMARKERS
• N- TERMINAL Pro BNP
• Hyponatremia
- Neuro hormonally released Vasopressin
induced
- Strongly associated with RHF and poor
prognosis
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 stages1
• By recognizing and treating patients as early as possible,
disease progression may be delayed
• Without treatment, patients in WHO FC II can rapidly
deteriorate within 6 months to more advanced PAH as
evidenced by progression of symptoms.
TREATMENT STRATEGY
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Prevention
Screening of high risk patients
Optimize therapy for related disease
Supportive treatment ( aimed at consequences
of PAH)
• Vascular targeted therapy (aimed at reducing/
reversing vasoconstriction, proliferation)
• Surgical ( atrial septostomy, lung transplantation)
SUPPORTIVE
Anticoagulants - warfarin for prevention against in situ thrombosis
INR goal is 2-2.5
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
VASCULAR TARGETED THERAPIES
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Prostacyclin pathway
Beraprost (PO)
Ilioprost (Inhaled)
Epoprostenol (IV)
Treprostinil (SQ,IV, inhaled)
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NO pathway
Dipyridamole(PO)
Nitric oxide (inhaled)
Sildenafal (PO)
Taladafil (PO)
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Endothelin pathway
Ambrisentan (PO) ER-A antagonist
Bosentan(PO) non selective
CALCIUM CHANNEL BLOCKERS
• Never given empirically
• Reserved 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 deterioration
treatment escalated
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
COMBINATION THERAPY
• Maximize therapy while minimize toxicity
• 8 trials with 1600 patients published
various combinations
6MWT as the primary endpoint 12 -16 weeks
showed only modest improvement
• Recommended for Class III and IV who fail to
improve or class II with deterioration
SURGICAL OPTIONS
• Atrial septostomy
-Reduced RVEDP, increased CI, increased exercise capacity at
expense of decreased PaO2
-Option in patients unresponsive to max Rx
-Bridge to transplantation
• Lung transplantation
-Typically bilateral lung transplantation
-Heart-lung transplantation in patients with PAH secondary to
congenital heart disease
• Pulmonary thromboendarterectomy for patients with CTEPH
TREATMENT ALGORITHM FOR PAH
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
PAH and PREGNANCY
• Mortality rate approaches 30%
• Contraception is strongly recommended in
women of child bearing age with PAH
• Mechanical contraception (IUD) or surgical
sterilization is recommended
Summary
• PAH is a complex disease involving vascular proliferation, inflammation &
remodeling
• Unexplained dyspnea should be worked up in a stepwise fashion
• Good history and physical can give clues towards the diagnosis and
etiology
• Diagnosis in early stage leads to early treatment and better outcome.
• Echocardiogram is an internationally recommended screening tool.
• Right heart catheterization is needed for definitive diagnosis
• Calcium channel blockers are to not be used empirically
• Vascular targeted therapies now available and improve quality of life and
mortality.
• Mortality remains high even with the modern pharmacologic
interventions
• Pregnancy is contraindicated because of high mortality
REFRENCES
• Pulmonary Board review 25th edition
• www.phaonline.org
• Murray and nadel’s “Textbook of respiratory
medicine” 5th edition.
• Gilead sciences inc.