Pulmonary
Hypertension 2009
Jimmy Ford, MD
Pulmonary Hypertension Program
Division of Pulmonary and Critical
Care Medicine
UNC Chapel Hill
How Common is It?
Hypertension 
Relatively Common
Pulmonary Arterial
Hypertension  Relatively
Uncommon
Pulmonary
What is the Difference?

Pulmonary Hypertension = A general term used to
describe elevated pressure in the pulmonary vascular
bed, not describing where the “lesion” is.
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Pulmonary Arterial Hypertension = A term that
describes elevated pressure in the pulmonary
vasculature, limited to the arteries/arterioles, and due to
an intrinsic abnormality in the pulmonary arterial bed.
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Definition of PAH by WHO
2008 Dana Point/ACC
Consensus
Required:
Mean PAP ≥ 25 mm Hg, no longer an exercise
definition.
 PCWP ≤ 15 mm Hg
 PVR ≥ 3 Wood Units (240 dynes.sec.cm-5)
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A Word about Hemodynamics
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The right heart catheterization is crucial.
Diagnosis and/or treatment choices should
almost never be made based upon
echocardiography alone, it is a screening tool.
Exercise and volume challenges are helpful
during RHC to refine your diagnosis
Useful calculations:
mPAP = 1/3 sPAP + 2/3 dPAP
 PVR = mPAP – PCWP / C.O.
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PAH
•The term PAH represents true
pulmonary ateriopathy,
characterized by:
•In situ microthrombosis
•Plexiform lesion formation
•Leads to progressive increase in
pulmonary vascular resistance and
culminates in right heart failure and
death
•Three key pathogeneses:
•Relative decrease in
bioavailability of NO
•Relative increase in serum
endothelin-1
•Relative deficieny of
PGI2/excess of thromboxane
A2
•The term PH represents increased
PAP but not due to intrinsic
vascular disease
The Progression of PAH
Classification of PH
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The current classification system groups
together forms of pulmonary hypertension
based on similarities in their pathophysiologies
and responses to treatment.
Important to classify patients correctly to ensure
therapeutic choices are appropriate.
Current classification system revised in 2008,
Dana Point, WHO 4th World Symposium on
PH.
Group 1 -- PAH
Groups 2-5 -- PH
Symptoms of PAH
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Dyspnea
Fatigue
Near syncope/syncope
Chest pain
Palpitations
LE edema
60%
19%
13%
7%
5%
3%
Reasons to Suspect PAH
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Unexplained dyspnea despite multiple
diagnostic tests
Typical symptoms (look for Raynaud’s)
Comorbid conditons:
CREST, liver disease, HIV, sickle cell
 Family history of PAH
 History of stimulant/anorexigen use
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Why is it missed?
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Young patients with non-specific sxs with nl
CXR and EKGs often attributed to
somatization and treated with reassurance
Lack of therapies in earlier era lead to attitude
of indifference with regard to aggressive
workup
Comorbid conditions with similar sxs
Physical exam clues
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Telengectasias
Calcinosis
Raynaud’s
Palmar erythema/stigmata of liver dz
JVD
RV heave
Murmur TR, VSD/ASD
Loud P2 (can hear 2nd heart sound clearly at
apex)
Clubbing
LE edema
Diagnostic Work-up
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Labs
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Autoimmune serologies
Markers of liver synthetic function
HIV serologies when dictated by history
EKG
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Not sensitive enough to be a screen but can help guide dx
workup
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RVH 87% of PH
RAD 79% of PH
RAE: p wave > 2.5 mm in II, III, aVF
Diagnostic Work-up
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Chest x-ray
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Not sensitive enough to screen
Attenuated “motheaten” peripheral vasculature
Enlarged PAs (especially right)
Echocardiogram
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Order for screening when clinical suspicion exists
Order for standard interval screening in selected groups:
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Family of those with IPAH or with known BMPR2 mutation
Scleroderma spectrum, other CTD
CHD pts
Pre-liver transplant
Echocardiogram Findings
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Increased sPAP / TR jet
Right atrial and ventricular hypertrophy
Flattening of interventricular septum
Small LV dimension
Dilated PA
Pericardial effusion
 Poor prognostic sign
 RA pressure so high it impedes normal drainage from
pericardium
 Do not drain, usually does not induce tamponade since RV
under high-pressure and non-collapsible
Always Rule out CTEPH
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Must be excluded in every case of PAH
Potentially surgically remediable
 1 center with most experience = UCSD
V/Q scan is preferred screening test, not PE protocol
CT (this is best for acute emboli).
In chronic thromboembolic disease, at least one (and
more commonly, several) segmental or larger
mismatched ventilation-perfusion defects are present.
Formal angiography will be done before surgical
procedure if V/Q positive
CTEPH
CTEPH Post-op
Right Heart Cath
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Essential for firm diagnosis:
Helps to not dx people with PAH that do not have
it!
 Vasoreactivity testing
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NO, Flolan, Adenosine—drop in mPAP by 10 mmHg to
value < 40 mmHg
 Predicts CCB response
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Evaluate for septal defects
 Shed light on the issue of diastolic dysfunction
 Interpret data in context of patient’s volume status
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How do we Treat Them?
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General measures:
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Avoid pregnancy
Contraception imperative
 Maternal mortality 30%
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Immunizations for respiratory illnesses
Influenza & pneumonia vaccinations
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Minimize valsalva maneuvers—increase risk of
syncope
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Cough, constipation, heavy lifting, etc
Classes of therapy
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Medical
 Diuretics
 Coumadin (IPAH, Anorexigen)
 Oxygen
 PAH specific therapy
Surgical therapy
 Atrial septostomy
 Lung transplantation
Diuretics
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Principally to treat edema from right heart
failure
Ventricular interdependence—ensure LV output
preserved.
May need to combine classes
-Thiazide and loop diuretics
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Careful to avoid too much pre-load reduction
Patients often require large doses of diuretics
Coumadin
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Studies only show benefit in IPAH patients,
based on improved survival.
Other PAH groups not as clear, use in them
considered expert opinion.
Generally, keep INR 1.5-2.5.
Thought to lessen in-situ thrombosis
Oxygen
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Formal assessment of nocturnal and exertional
oxygenation needs.
Minimize added insult of hypoxic vasoconstriction
Keep oxygen saturation ≥90%
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Exclude nocturnal desaturation
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May be impossible with large right to left shunt
Overnight oximetry
Rule out concomitant obstructive sleep apnea and
hypoventilation syndromes
WHO functional classification
PAH
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Class I: No limitation in physical activity. Ordinary
physical activity does not cause undue dyspnea or fatigue,
chest pain or near syncope.
Class II: Slight limitation in physical activity. Ordinary
physical activity causes undue dyspnea or fatigue, chest
pain or near syncope.
Class III: Marked limitation in physical activity. Less than
ordinary physical activity causes undue dyspnea or fatigue,
chest pain or near syncope.
Class IV: Inability to perform any physical activity
without symptoms. Signs of right heart failure. Dyspnea
and/or fatigue may be present at rest. Syncope.
PAH-Specific Therapies
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Calcium channel blockers
Endothelin receptor antagonists (ERAs)—
bosentan, ambrisentan
Phosphodiesterase (type 5) inhibitors (PDE 5I)—sildenafil, tadalafil
Prostanoids—epoprostenol, treprostinil,
iloprost
Calcium Channel Blockers
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Use only when demonstrated vasoreactivity in
RHC (about 10% or less of patients)
Diltiazem or nifedipine preferred.
Titrate up to maximum tolerated dose.
Systemic hypotension may prohibit use
Only 50% of patients maintain response to
CCB.
Not in FC IV patients or severe right heart
failure
Endothelin Receptor Antagonists
(ETRA)
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Targets relative excess of endothelin-1 by blocking
receptors on endothelium and vascular smooth muscle
Bosentan (Tracleer, 5 yrs) and ambrisentan (Letairis, 1
yr)
Ambrisentan is ET-A selective.
Both show improvement in 6MWD and time to clinical
worsening.
Monthly transaminase monitoring required for both
Annual cost about $40,000
Bosentan (Tracleer)
• 215 patients
70% IPAH
92% Class III
• Week 16:
•36 meter
Improvement
•44 meter
treatment
effect
1Adapted from Rubin LJ et al. N Engl J Med 2002;346:896-903
Bosentan (Tracleer)
Improved Hemodynamics
CI
mRAP
PVR
PAP
Δ + 1.0 L/min/m2
Δ - 6.2 mm Hg
(p=0.001)
Δ - 415dyn/sec/cm-5
(p=0.001)
Δ - 6.7 mm Hg
(p<0.02)
(p=0.001 )
+4.9 ± 4.6
Change from baseline (%)
50%
40%
30%
+191 ± 235
+0.5 ± 0.5
20%
+5.1 ± 8.8
10%
0%
-1.6 ± 5.1
-10%
-20%
-1.3 ± 4.1
-0.5 ±0.5
-223 ± 245
-30%
Placebo
Tracleer
One patient in each treatment group had no valid week 12 assessment and was not included in the analysis.
Adapted from Channick, et al. Lancet 2001
Bosentan (Tracleer)
Potential for serious liver injury (including very rare cases of unexplained hepatic
cirrhosis after prolonged treatment)
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Tracleer causes at least a 3-fold increase in aminotransferases (ALT and AST) in
about 11% of patients and may be accompanied by an elevation of bilirubin in a
small number of cases
 Teratogenic and lowers sperm
 Significant drug interactions
 Glyburide inhibits bosentan metabolism
 Bosentan induces metabolism of oral
contraceptives, warfarin, and statins
 Calcineurin inhibitors (cyclosporin A,
tacrolimus), protease inhibitors, amiodarone, ketoconozole
Bosentan (Tracleer)
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Oral dosing
 Initiate at 62.5 mg BID for first 4 weeks
 Increase to maintenance dose of 125 mg BID thereafter
 Initiation and maintenance dose of 62.5 mg BID
recommended for patients >12 years of age with body
weight <40kg
No dose adjustment required in patients with renal
impairment
No predetermined dose adjustments required for
concomitant warfarin administration*
Ambrisentan (Letairis)
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5 or 10 mg once daily
Less risk of transaminase elevation (about 1%),
but monthly monitoring still required
No dose adjustment of coumadin needed
No drug-drug interaction
Improved 6 MWD in pivotal study
PDE-5 inhibitors
Adapted from Hill, N. NJ Fellows Conf in PAH 12/2/06
Sildenafil (Revatio)
Adapted from Hill, N. NJ Fellows Conf in PAH 12/2/06
Sildenafil (Revatio)
Adapted from Hill, N. NJ Fellows Conf in PAH 12/2/06
Sildenafil (Revatio)
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Safety
Side effects: headaches, epistaxis, and hypotension
(transient)
 Sudden hearing loss
 Drug interaction with nitrates
 FDA approved dose is 20 mg tid
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Higher doses often used given hemodynamic findings.
Adcirca/Tadalafil Improves 6MWT and
Time to Clinical Worsening
6MWT Distance
TTCW Endpoint
P = 0.004
Adapted from Galie et al Circulation 2009.
P < 0.05
Prostacyclin analogues
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Epoprostenol, treprostinil, iloprost
Benefits
Vasodilation
 Platelet inhibition
 Anti-proliferative effects
 Inotropic effects
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Epoprostenol (Flolan)
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First PAH specific therapy available in the mid
1990’s
Lack of acute vasodilator response does not
correlate well with epoprostenol
unresponsiveness.
Very short half life = 2 minutes
Delivered via continuous infusion
Cost about $100,000/year
Epoprostenol (Flolan)
Adapted from Hill, N. NJ Fellows Conf in PAH 12/2/06
Epoprostenol (Flolan)
Adapted from Hill, N. NJ Fellows Conf in PAH 12/2/06
Epoprostenol (Flolan)
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Side effects: headache, jaw pain, flushing,
diarrhea, nausea and vomiting, flu-like
symptoms, and anxiety/nervousness
Complex daily preparation
Individualized dosing
Catheter complications
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Dislodgement/malfunction
Catastrophic deterioration
Embolization
Infection (3% deaths)
1 Flolan Flolan®[package [package insert]. Research Triangle Park, NC:GlaxoSmithKline;2002 insert].
Research Triangle Park, NC:GlaxoSmithKline;2002
2Rich S et al. Rich S et al. J Am College J Am College Cardiol Cardiol 1999;34:1184 1999;34:1184-87 87
McLaughlin V et al. McLaughlin V et al. Circulation Circulation 2002;106:1477 2002;106:1477-82 82
Treprostinil (Remodulin)
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Continuous subcutaneous
infusion or IV infusion
Longer t1/2 than flolan = 4
hours
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Less risk of rapid fatal
deterioriation if infusion stops
Significant site pain at infusion
site limits use
Adapted from Hill, N. NJ Fellows Conf in PAH 12/2/06
Treprostinil (Remodulin)
Adapted from Hill, N. NJ Fellows Conf in PAH 12/2/06
Treprostinil (Remodulin)
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Intravenous treprostinil
Hemodynamic improvements and 6MWD
improvements 1
 No site pain
 Risk of catheter related bloodstream infection and
embolic phenomenon
 Recent concerns about increased gram-negative
bloodstream infections (CDC MMWR March 2,
2007 / 56(08);170-172)
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1Tapson VF et al. Chest 2006;129:683-88
Iloprost (Ventavis)
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Inhaled prostacyclin
Administered 6-9 times
daily via special nebulizer
Reported risk of
morning syncope
Iloprost (Ventavis)
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Improvements in 6MW, functional class and hemodynamics
observed
Olschewski H et al. N Engl J Med 2002;347:322-29
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Safety and side effects
Potential for increased hypotensive effect
with antihypertensives
 Increased risk of bleeding, especially with
co-administration of anticoagulants
 Flushing, increased cough, headache, insomnia
 Nausea, vomiting, flu-like syndrome
 Increased liver enzymes
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Inhaled Treprostinil (Tyvaso)
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Inhaled prostacyclin
Administered 4 times daily
Proprietary nebulizer
TRIUMPH study showed
improvements in 6MWD
ACC 2009 Treatment Guidelines
Following Response to Therapy
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Six minute walk test
Echocardiogram
Right heart catheterization
BNP
Functional class
Acute Decompensations
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Patients with advanced PAH may present acutely with
volume overload, marginal blood pressure, and, at
times, elevated creatinine, related either to an acute
process or simply worsening RV failure.
In the decompensated patient, elevated RV volume
leads to septal shift, with reduced left ventricular enddiastolic volume and low cardiac output.
Treatment of the acutely ill patient with PAH should
include careful evaluation for secondary causes of
decompensation such as a low-grade line infection (for
those on an intravenous therapy) or pulmonary
thromboembolism.
Acute Decompensations
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Many patients are volume overloaded at presentation,
and diuresis, even in the setting of marginal cardiac
output and low blood pressure, may be required.
In some cases, support with inotropes or pressors is
necessary: animal data suggest a better hemodynamic
response with sympathomimetic agents such as
dobutamine, norepinephrine, and dopamine rather than
vasopressin or phenylephrine; milrinone also has
favorable effects on cardiac output but may lead to
excessive hypotension.
Summary
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Make sure to differentiate PAH from PH
Determine etiology of PAH as best as possible
Refer early to specialist if you find it
Don’t treat without a RHC
Treat agressively, don’t settle for “stability”
UNC Pulmonary Hypertension
Program
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Jimmy Ford, MD
Robert Aris, MD
Sarah McGee, Research Coordinator
11 clinical trials ongoing
Right heart catheterization service
Formal clinic at ACC