JAMES L. ANGTUACO, M.D., DPPS,DPSPC, FPCC
U.P. College of Medicine Intarmed Class 1992
Pediatric Residency, UP-PGH 1993-95
Fellowship, Pediatric Cardiology, UP-PGH 1996-99
Fellowship, Pediatric Cardiology, New Children’s Hospital of Westmead, Sydney Australia,
1999-2000
Positions:
Chair, CME Programs, Chinese General Hospital, 2010-present
Head, OPD Section of Pediatric Cardiology, SLMC 2009-present
Member, Committee on Research Philippine Pediatric Society, 2012Chair, Research Committee, Chinese General Hospital, 2004 – 2010
Member, Residency Training Committee, Chinese General Hospital, 2004-present
Faculty, San Beda College of Medicine (2006-present)
Vice President RF/ RHD Foundation of the Philippines (2012- )
Affiliations:
Metropolitan Medical Center
St. Luke’s Medical Center
Our Lady of Lourdes Hospital
Chinese General Hospital
Manila Adventist Medical Center
Manila Doctor’s Hospital
Pulmonary Hypertension:
Guidelines in the Diagnosis
and Treatment
James L. Angtuaco, M.D., DPPS, DPSPC, FPCC
Pediatric Cardiologist
DISCLAIMER
OBJECTIVES:
1. To discuss the definition of Pulmonary arterial
hypertension
2. To discuss the different pathology / pathobiology of
Pulmonary arterial hypertension
3. To describe the classifications of Pulmonary arterial
hypertension
4. To discuss the clinical presentations of Pulmonary
arterial hypertension
5. To discuss the different diagnostic modalities for
Pulmonary arterial hypertension
6. To discuss the different treatment modalities for
Pulmonary arterial hypertension
Pulmonary Hypertension
• Definition:
– increase in mean pulmonary arterial pressure > 25
mmHg at rest as assessed by right heart
catheterization
– normal mean pulmonary arterial pressure is 14+3
mmHg. with an upper limit of ~20 mmHg.
– gray zone : 21-24 mmHg.
CLINICAL CLASSIFICATION OF PULMONARY ARTERIAL
HYPERTENSION
(The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of
Cardiology and the European Respiratory Society, endorsed by the International Society of Heart & Lung
Transplantation 2009)
European Heart Journal 2009
• GROUP 1: PULMONARY ARTERIAL
HYPERTENSION
– idiopathic
– Heritable
• BMPR2 (bone morphogenesis protein receptor 2 gene)
• ALK1 (activin receptor like kinase type 1 gene), endoglin
(with or without hereditary hemorrhagic telangiectasia)
• Unknown
– Drugs and toxins induced (weight loss drugs)
CLINICAL CLASSIFICATION OF PULMONARY ARTERIAL
HYPERTENSION
(The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of
Cardiology and the European Respiratory Society, endorsed by the International Society of Heart & Lung
Transplantation 2009)
European Heart Journal 2009
• GROUP 1: PULMONARY ARTERIAL
HYPERTENSION
– associated with:
•
•
•
•
•
•
connective tissue disease
HIV infection
portal hypertension
Congenital Heart Disease
Schistosomiasis
Chronic hemolytic anemia
– Persistent pulmonary hypertension of the newborn
CLINICAL CLASSIFICATION OF PULMONARY ARTERIAL
HYPERTENSION
(The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of
Cardiology and the European Respiratory Society, endorsed by the International Society of Heart & Lung
Transplantation 2009)
European Heart Journal 2009
• GROUP 1’ : PULMONARY VENO-OCCLUSIVE
DISEASE WITH PULMONARY CAPILLARY
HEMANGIOMATOSIS
CLINICAL CLASSIFICATION OF PULMONARY ARTERIAL
HYPERTENSION
(The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of
Cardiology and the European Respiratory Society, endorsed by the International Society of Heart & Lung
Transplantation 2009)
European Heart Journal 2009
• GROUP 2: PULMONARY HYPERTENSION DUE
TO LEFT HEART DISEASE
– systolic dysfunction
– diastolic dysfunction
– valvular disease
CLINICAL CLASSIFICATION OF PULMONARY ARTERIAL
HYPERTENSION
(The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of
Cardiology and the European Respiratory Society, endorsed by the International Society of Heart & Lung
Transplantation 2009)
European Heart Journal 2009
• GROUP 3: PULMONARY HYPERTENSION DUE TO
LUNG DISEASE AND/ OR HYPOXIA
– chronic obstructive pulmonary disease
– interstitial lung disease
– other pulmonary diseases with mixed restrictive and
obstructive pattern
– sleep-disordered breathing
– alveolar hypoventilation disorders
– chronic exposure to high altitude
– developmental abnormalities
CLINICAL CLASSIFICATION OF PULMONARY ARTERIAL
HYPERTENSION
(The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of
Cardiology and the European Respiratory Society, endorsed by the International Society of Heart & Lung
Transplantation 2009)
European Heart Journal 2009
• GROUP 4: CHRONIC THROMBOEMBOLIC
PULMONARY HYPERTENSION (CTEPH)
CLINICAL CLASSIFICATION OF PULMONARY ARTERIAL
HYPERTENSION
(The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of
Cardiology and the European Respiratory Society, endorsed by the International Society of Heart & Lung
Transplantation 2009)
European Heart Journal 2009
• GROUP 5 : PULMONARY HYPERTENSION WITH
UNCLEAR AND/OR MULTIFACTORIAL MECHANISMS
– hematologic disorders : myeloproliferative disorders,
splenectomy
– systemic disorders : sarcoidosis, pulmonary Langerhans cell
histiocytosis, lymphangioleiomyomatosis,
neurofibromatosis, vasculitis
– metabolic disorders: glycogen storage disease: Gaucher
disease, thyroid disorders
– others: tumoural obstruction, fibrosing mediastinitis, chronic
renal failure on dialysis
PATHOLOGY OF PULMONARY
HYPERTENSION
• Group 1: PAH
– affects the distal pulmonary arteries (<500 um in
diameter)
– medial hypertrophy
– intimal proliferation and fibrotic changes (concentric
and eccentric)
– adventitial thickening with moderate perivascular
inflammatory infiltrates
– plexiform dilated lesions
– thrombotic lesions
– PULMONARY VEINS ARE CLASSICALLY UNAFFECTED
Pietra GG et. al. JACC 2004
Tuder RM et. al. JACC 2009
PATHOLOGY OF PULMONARY
HYPERTENSION
• Group 1’: Pulmonary Veno-Occlusive Disease
–
–
–
–
–
–
–
–
involves septal veins and pre-septal venules
occlusive fibrotic lesions
venous muscularization
frequent capillary proliferation (patchy)
pulmonary edema
occult alveolar hemorrhage
lymphatic dilatation / lymph node enlargement
distal pulmonary arteries have medial hypertrophy,
intimal fibrosis
Pietra GG et. al. JACC 2004
Tuder RM et. al. JACC 2009
PATHOLOGY OF PULMONARY
HYPERTENSION
• Group 2: Left Heart Disease
– enlarged, thickened pulmonary veins
– pulmonary capillary dilatation
– interstitial edema
– alveolar hemorrhage
– lymphatic vessel and lymph node enlargement
– distal pulmonary artery may have medial
hypertrophy and intimal fibrosis
Pietra GG et. al. JACC 2004
Tuder RM et. al. JACC 2009
PATHOLOGY OF PULMONARY
HYPERTENSION
• Group 3: PAH due to lung disease
– medial hypertrophy and intimal obstructive
proliferation of the distal pulmonary arteries
– variable degree of destruction of the vascular bed in
emphysematous or fibrotic areas
Pietra GG et. al. JACC 2004
Tuder RM et. al. JACC 2009
PATHOLOGY OF PULMONARY
HYPERTENSION
• Group 4: CTEPH
– organized thrombi attached to the medial layer of
the elastic pulmonary arteries
– may cause complete occlusion, stenosis, formation
of webs or bands
– collateral vessels from bronchial, costal,
diaphragmatic or coronary arteries may develop to
reperfuse the distal segments
Pietra GG et. al. JACC 2004
Tuder RM et. al. JACC 2009
PATHOLOGY OF PULMONARY
HYPERTENSION
• Group 5: Idiopathic
– unclear pathology
Pietra GG et. al. JACC 2004
Tuder RM et. al. JACC 2009
PATHOBIOLOGY OF
PULMONARY HYPERTENSION
• Group 1: PAH
– vasoconstriction, proliferative, and obstructive
remodelling of pulmonary vessel wall
– inflammation and thrombosis
– abnormal function or expression of potassium channels
in smooth muscle cells
– endothelial dysfunction
– impaired production of vasodilator and anti-proliferative
agents (e.g. NO and prostacyclin)
– overexpression of vasoconstrictor & proliferative
substances (e.g.. thromboxane A2 and endothelin-1)
Humbert M. et. al. JACC 2004
Hassoun PM et. al. JACC 2009
Morrell N. et. al JACC 2009
PATHOBIOLOGY OF
PULMONARY HYPERTENSION
• Group 1: PAH
– elevated vascular tone
– promote vascular remodelling by proliferative
changes (includes endothelial, smooth muscle cells,
and fibroblasts)
– increased production of extracellular matrix
including: collagen, elastin, fibronectin, and
tenascin
– prothrombotic activity
Humbert M. et. al. JACC 2004
Hassoun PM et. al. JACC 2009
Morrell N. et. al JACC 2009
PATHOBIOLOGY OF
PULMONARY HYPERTENSION
• Group 2: PAH due to left heart disease
– vasoconstrictive reflexes from stretch receptors in
the left atrium and pulmonary veins
– endothelial dysfunction of pulmonary arteries 
favour vasoconstriction and proliferation of vessel
wall cells
Humbert M. et. al. JACC 2004
Hassoun PM et. al. JACC 2009
Morrell N. et. al JACC 2009
PATHOBIOLOGY OF
PULMONARY HYPERTENSION
• Group 3: PAH due to lung disease
– hypoxic vasoconstriction
– mechanical stress of hyperinflated lungs
– loss of capillaries
– inflammation and toxic effects of cigarette smoke
– endothelin derived vasoconstrictor – vasodilator
imbalance
Humbert M. et. al. JACC 2004
Hassoun PM et. al. JACC 2009
Morrell N. et. al JACC 2009
PATHOBIOLOGY OF
PULMONARY HYPERTENSION
• Group 4: CTEPH
– abnormalities in the clotting cascade, endothelial
cells, and platelets
– shear, stress, pressure, inflammation, and release of
cytokines and vasculotropic substances
Humbert M. et. al. JACC 2004
Hassoun PM et. al. JACC 2009
Morrell N. et. al JACC 2009
PATHOBIOLOGY OF
PULMONARY HYPERTENSION
• Group 5:
– unknown
Humbert M. et. al. JACC 2004
Hassoun PM et. al. JACC 2009
Morrell N. et. al JACC 2009
DIAGNOSIS
• CLINICAL PRESENTATION
– NON-SPECIFIC SYMPTOMS:
•
•
•
•
•
•
•
breathlessness
fatigue
weakness
angina
syncope
abdominal distension
symptoms at rest only in very advanced cases
Rich S et. al Ann Intern Med 1987
DIAGNOSIS
• CLINICAL PRESENTATION
– SIGNS:
•
•
•
•
left parasternal lift
accentuated P2
holosystolic murmur of tricuspid regurgitation
diastolic murmur of pulmonary regurgitation
Rich S et. al Ann Intern Med 1987
DIAGNOSIS
• CLINICAL PRESENTATION
– SIGNS in more advanced cases:
•
•
•
•
•
•
S3 gallop
jugular vein distension
hepatomegaly
peripheral edema
ascites
cool extremities
Gaine SP et al. Lancet 1998
DIAGNOSIS
• CLINICAL PRESENTATION
– ASSOCIATED SIGNS:
• telangiectasia, digital ulceration, sclerodactyly
(SCLERODERMA)
• inspiratory crackles (INTERSTITIAL LUNG DISEASE)
• spider nevi, testicular atrophy, palmar erythema
(CHRONIC LIVER DISEASE)
• clubbing (IPAH, CHD, PVOD)
Rich S et. al Ann Intern Med 1987
DIAGNOSIS
• ELECTROCARDIOGRAM:
– suggestive or supportive evidence
•
•
•
•
RV hypertrophy (87%) and strain
Right axis deviation (79%)
RA dilatation
atrial flutter and atrial fibrillation (ADVANCED STAGES)
– absence does NOT rule out disease
– insufficient sensitivity (55%) and specificity (70%)
Rich S et. al Ann Intern Med 1987
DIAGNOSIS
• CHEST RADIOGRAPH:
– central pulmonary arterial dilatation
– pruning (loss of) distal pulmonary vessels
– RA and RV enlargement (ADVANCED STAGES)
– can be used to exclude moderate to severe lung
diseases or pulmonary venous hypertension due to
left heart disease
– cannot assess the degree of PAH
Rich S et. al Ann Intern Med 1987
DIAGNOSIS
• PULMONARY FUNCTION TESTS and ABG
– decreased lung diffusion capacity of carbon monoxide
(40-80% of predicted)
– mild to moderate reduction of lung volume
• may indicate interstitial lung disease if coupled with above
–
–
–
–
–
arterial oxygen tension is normal or slightly lower at rest
arterial carbon dioxide tension is decreased
irreversible airflow obstruction
increased residual volumes
overnight oximetry or polysomnography is with OSA
DIAGNOSIS
• ECHOCARDIOGRAPHY
– transthoracic echocardiography
– estimation of PAP:
• peak pressure gradient of TR = 4x(TR velocity)2
• PAP = PG TR jet + estimated RA Pressure
– RA Pressure is estimated at 5-10 mmHg.
• mPAP = 0.61 x PA systolic pressure + 2 mmHg
– may use contrast echocardiography if difficult to assess
TR
– few studies have been done to find an accurate
correlation between these and RHC
Fisher MR et. al. Am J. Resp Crit Care 2009
DIAGNOSIS
• ECHOCARDIOGRAPHY
– other findings:
increased velocity of pulmonary valve regurgitation
short acceleration time of RV ejection into the PA
increased dimension of right heart chambers
abnormal shape and function of the interventricular
septum
• increased RV wall thickness
• dilated main PA
•
•
•
•
Murkejee D et al. Rheumatology 2004
VENTILATION-PERFUSION
SCAN
• useful for potentially treatable CTEPH
• higher sensitivity than CT
• normal or low-probability VQ scan
– excludes CTEPH (sensitivity 90-100% /
specificity 94-100%)
Tunariu N. et. al. J Nucl Med 2007
HIGH-RESOLUTION CT, CONTRASTENHANCED CT, AND PULMONARY
ANGIOGRAPHY
• detailed view of lung parenchyma  interstitial
lung disease and emphysema
• suspected PVOD: interstitial edema with diffuse
central central ground-glass opacification and
thickening of interlobular septa;
lymphadenopathy and pleural effusion
Resten A et. al. Am J Roentgenol 2004
HIGH-RESOLUTION CT, CONTRASTENHANCED CT, AND PULMONARY
ANGIOGRAPHY
• contrast CT angiography of the PA
– to check for evidence of surgically accessible
CTEPH
– complete obstruction, bands and webs, and intimal
irregularities (similar to digital subtraction
angiography)
• traditional pulmonary angiography
– required to identify patients who may benefit from
pulmonary endarterectomy
– evaluation for vasculitis or pulmonary AVMs
Dartevelle P et. al. Eur Respir J 2004
CARDIAC MRI
• image RV size, morphology and function
• non-invasive assessment of blood flow : including
–
–
–
–
stroke volume
cardiac output
distensibility of PA
RV mass
• decreased stroke volume, increased RV enddiastolic volume* and decreased LV end-diastolic
volume (predictors of poor prognosis)
* most appropriate marker
Torbicki A et. al. Eur Heart J 2007
BLOOD TESTS AND
IMMUNOLOGY
• serologic test to identify CTD, HIV and hepatitis
• limited scleroderma
– anti-centromere antibodies, dsDNA, anti-Ro, U3-RNP,
B23, Th/To, U1-RNP
• diffuse scleroderma
– U3-RNP
• SLE
– anti-cardiolipin antibodies
• Thrombophilia in CTEPH
– anti-phospholipid antibodies, lupus anticoagulant, anticardiolipin antibodies
Rich S et. al. JACC 1986
Chu JW et. al. Chest 2002
ABDOMINAL ULTRASOUND
• liver cirrhosis and / or portal hypertension
Albrecht T. et. al. Lancet 1999
RIGHT HEART
CATHETERIZATION
• REQUIRED to diagnose PAH
– assess severity of hemodynamic impairment
– test for vasoreactivity of the pulmonary circulation
– PAP (systolic, diastolic, mean), right atrial pressure,
PWP, and RV Pressure
– Cardiac output
RIGHT HEART
CATHETERIZATION
• REQUIRED to diagnose PAH
– to identify who may benefit from long-term therapy
with CCBs.
– acute vasodilator challenge with short-acting, safe,
and easy to administer drugs with no or limited
systemic effects
• nitric oxide
• intravenous epoprostenol
• intravenous adenosine (risky for systemic vasodilator
effect)
Galie N et. al Am J. Cardiol 1995
RIGHT HEART
CATHETERIZATION
• REQUIRED to diagnose PAH
– positive acute response:
• reduction mean PAP > 10 mmHg. to reach an absolute
value of mean PAP < 40 mmHg. ; with
• an increased or unchanged Cardiac Output
• long-term responders to CCBs
Sitbon O et. al Circ 2005
exertional dyspnea
syncope
angina
progressive limitation of
exercise capacity
Bone Morrphogenetic
Protein Receptor 2,
Activin receptor –Like
Kinase type 1, Endoglin
Family History
TREATMENT
• GENERAL MEASURES:
– degree of social isolation
– encourage patients and family members to join
patient support groups  positive effect on coping,
confidence, outlook
TREATMENT
• GENERAL MEASURES:
– PHYSICAL ACTIVITY and SUPERVISED
REHABILITATION:
• active within symptom limits (mild breathlessness is
acceptable; avoid severe breathlessness, exertional
dizziness, or chest pain)
• training program to improve exercise performance
• avoid excessive physical activities
• when physically deconditioned supervised exercise
rehabilitation
Mereles D. et. al. Circulation 2006
TREATMENT
• GENERAL MEASURES:
– PREGNANCY, BIRTH CONTROL, AND POSTMENOPAUSAL HORMONAL THERAPY
• pregnancy : 30-50% mortality in patients with PAH
• barrier method: unpredictable but safe
• progesterone only preparations e.g.
medroxyprogesterone acetate and etonogestrel are
effective
• NOTE: endothelin receptor antagonist bosentan reduces
efficacy of contraceptives
• Mirena coil is effective but can cause Vasovagal reaction
The Task Force on the Management of Cardiovascular Disease During Pregnancy
Eur Heart J 2003
Beclard E. et. al Eur Heart J 2009
TREATMENT
• GENERAL MEASURES:
– TRAVEL
• may need in –flight O2 if WHO-FC III/IV and arterial blood
O2 <60 mmHg.
• 2L / min. sufficient
• avoid going to altitudes above 1500-2000 m without
supplemental O2
• travel with a written information about the PAH
TREATMENT
• GENERAL MEASURES:
– PSYCHOSOCIAL SUPPORT
• REFER for Psychiatric evaluation if with severe anxiety
and depression
• Patient Support Groups
– INFECTION PREVENTION
• influenza and pneumococcal vaccine
– ELECTIVE SURGERY
• suggest epidural vs. general anesthesia
• shift to i.v. or nebulized meds then shift back to oral
Rich S. eta. al Ann Intern Med 1998
TREATMENT
• SUPPORTIVE THERAPY
– Oral Anticoagulation
• its use is based on the non-specific risk for venous
thromboembolism (e.g. heart failure and immobility)
versus the risk of bleeding (e.g. portopulmonary
hypertension)
• useful in patients with IPAH, heritable PAH, and PAH due
to anorexigens
Fuster V et. al Circ 1984
TREATMENT
• SUPPORTIVE THERAPY
– Diuretics
• no RCTs on its use
• benefit in fluid overloaded patients with raised CVP,
hepatic congestion, ascites, and peripheral edema
• monitor renal function and blood biochemistry
• avoid hypokalemia and decreased intravascular volume
TREATMENT
• SUPPORTIVE THERAPY
– Oxygen
• no RCTs on its use on a long-term basis
• advise to maintain an O2 arterial blood pressure of > 60
mmHg. at least 15h/day
– Digoxin
• improves cardiac output acutely in IPAH
• efficacy is unknown when taken chronically
• slow ventricular rate in atrial tachyarrhythmia
Weitzenblum E. et. al. Am Rev Respir Dis 1985
Rich S. Chest 1998
TREATMENT
• SPECIFIC DRUG THERAPY
– CALCIUM CHANNEL BLOCKERS (CCBs)
• choice depends on baseline heart rate
• relative bradycardia favouring NIFEDIPINE and
AMLODIPINE; relative tachycardia favouring DILTIAZEM
• daily doses in IPAH : 120-240 mg. for NIFEDIPINE; or 240720 mg. in DILTIAZEM, or 20 mg. in AMLODIPINE
• low initial doses: 30 mg. Nifedipine slow release BID, or
60 mg. Diltiazem TID, or 2.5 mg. Amlodipine OD
– cautiously increase to maximum tolerated dose
– care for systemic hypotension and peripheral edema
Sitbon O et. al. Circ 2005
TREATMENT
• SPECIFIC DRUG THERAPY
– PROSTANOIDS
• Prostacyclin produced in endothelial cells inducing
potent vasodilation of all vascular beds
• most potent endogenous inhibitor of platelet aggregation
• potent cytoprotective and antiproliferative activities
TREATMENT
• SPECIFIC DRUG THERAPY
– PROSTANOIDS
• EPOPROSTENOL
– freeze dried preparation dissolved in alkaline buffer for IV
infusion
– short half-life (3-5 mins.)
– stable at room temperature for only 8 hours
– administered continuously via infusion pump and a permanent
tunnelled catheter
– improves symptoms, exercise capacity and hemodynamics
– only treatment showing improvement in survival in IPAH
Barst J et. al. NEJM 1996
TREATMENT
• SPECIFIC DRUG THERAPY
– PROSTANOIDS
• EPOPROSTENOL
– initial dose: 2-4 ng/kg/min.
– doses increasing at a rate limited by the side effects (flushing,
headache, diarrhea, leg pain)
– optimal dose : 20-40 ng/kg/min.
– serious adverse events: pump malfunction, local site infection,
catheter obstruction, sepsis
– avoid abrupt interruption of infusion  rebound PH with
symptomatic deterioration and even death
McLaughlin V et al. Circ 2002
TREATMENT
• SPECIFIC DRUG THERAPY
– PROSTANOIDS
• ILOPROST
– STABLE prostacyclin analogue (i.v., oral, and aerosol)
– inhaled route advantageous  selective for pulmonary
circulation
– daily repetitive inhalation 2.5 – 5 ug/inhalation 6-9x/day ; median
dose 30 ug/day
– increase in exercise capacity and improvement of symptoms,
PVR, and clinical events
– iv as effective as Epoprostenol, but oral form has not been
assessed
AIR Olschewski H et al NEJM 2002
TREATMENT
• SPECIFIC DRUG THERAPY
– PROSTANOIDS
• TREPROSTINIL
– tricyclic benzidine analogue of epoprostenol
– stable at ambient temperature; iv. and subQ routes
– initial dose: 1-2 ng/kg/min. SQ increasing dose limited by side
effects (local site pain, flushing, headache); optimal dose 20-80
ng/kg/min
– more convenient as reservoir is changed every 48 hours
– inhaled treprostinil improved exercise capacity with bosentan or
sildenafil
– improves exercise capacity and hemodynamics
Simmoneau G et al. Am J Respir Crit Care Med 2002
Barst RJ et. al. Eur Respir J 2006
TREATMENT
• SPECIFIC DRUG THERAPY
– PROSTANOIDS
• BERAPROST
–
–
–
–
improvement in exercise capacity
persists only for 3-6 months
no hemodynamic benefits
headache, flushing, jaw pain, diarrhea
Galie N et al. JACC 2002
TREATMENT
• SPECIFIC DRUG THERAPY
– ENDOTHELIN RECEPTOR ANTAGONIST
• Endothelin-1 exerts vasoconstrictor and mitogenic
effects by binding to distinct receptors (endothelin-A and
B) in the pulmonary vascular smooth muscle cells
• activation of Endothelin B receptors in endothelial cells
result in release of vasodilators and antiproliferative
substances (e.g. NO and prostacyclin)
TREATMENT
• SPECIFIC DRUG THERAPY
– ENDOTHELIN RECEPTOR ANTAGONIST
• BOSENTAN
– oral active dual (ETa and ETb) receptor antagonist for PAH (IPAH,
CTD associated PAH, Eisenmenger’s syndrome)
– start at 62.5 mg. twice daily and uptitrated to 125 mg. bid after 4
weeks
– improvement in exercise capacity, functional class,
hemodynamics, echocardiographic and doppler variables, and
time to clinical worsening
– increases in hepatic transaminases, reduction in hemoglobin,
and impaired spermatogenesis
Galie N et. al. Circ 2006
TREATMENT
• SPECIFIC DRUG THERAPY
– ENDOTHELIN RECEPTOR ANTAGONIST
• SITAXENTAN
– selective orally active ETa receptor antagonist for PAD (IPAH,
PAH associated with CTD or CHD)
– 100 mg once daily
– improvement in exercise capacity and hemodynamics
– 3-5% abnormal liver function
– interacts with warfarin need to reduce warfarin dose
Benza RL et. al. Chest 2008
TREATMENT
• SPECIFIC DRUG THERAPY
– ENDOTHELIN RECEPTOR ANTAGONIST
• AMBRISENTAN
– non-sulfonamide, propanoic acid-class selective ETa
– improves symptoms, exercise capacity, hemodynamics, and
time to clinical worsening
– 5 mg. once daily to 10 mg. once daily if tolerated at the initial
dose
– 0.8 – 3% with abnormal liver function test
– increased episode of peripheral edema
McGoon M et. al. Chest 2009
TREATMENT
• SPECIFIC DRUG THERAPY
– PHOSPHODIESTERASE TYPE 5 INHIBITORS
• inhibition of cGMP-degrading enzyme phosphodiesterase
type 5 vasodilation thru NO/cGMP pathway
• exerts antiproliferative effects
• significant pulmonary vasodilation occurs after 60
(Sildenafil), 75-90 (Tadalafil), and 40-45 (Vardenafil)
minutes
TREATMENT
• SPECIFIC DRUG THERAPY
– PHOSPHODIESTERASE TYPE 5 INHIBITORS
• SILDENAFIL
– orally active potent selective inhibitor
– 20 mg. tid with up titration to 40-80 mg. tid (where durability of
effects up to a year is seen) (Pediatric : 0.35 mg/kg/dose q 4H)/
(0.25 -1 mg/kg QID)
– improvement in exercise capacity, symptoms, and
hemodynamics
– headache, flushing, epistaxis
– 5-year survival rate 81%; more than 75% did not reach the
composite end-point of hospitalization for RV Failure and death
for a 5-year period
Palma G. et. al. Tex Heart Inst J 2011
Tilman H. et. al. Circ 2005
SUPER-2 Rubin L et. al. Chest 2012
Yanagisawa R et. al Circulation J 2012
TREATMENT
• SPECIFIC DRUG THERAPY
– PHOSPHODIESTERASE TYPE 5 INHIBITORS
• TADALAFIL
– once daily dispensed selective phosphodiesterase type 5
inhibitor
– 5, 10, 20, or 40 mg. OD (in Pediatrics: 1 mg/kg/day)
– favourable result in exercise capacity, symptoms,
hemodynamics, and time to clinical worsening
– side effects: headache, nausea, myalgia, nasal congestion,
flushing
Galie N. et. al. Circulation 2009
Takatsuki S. et. al. Pediatr Cardiol 2012
TREATMENT
• EXPERIMENTAL COMPOUNDS
– PHASE II and III studies:
•
•
•
•
•
•
•
NO-independent stimulators
cGMP activators
inhaled vasoactive intestinal peptide
non-prostanoid prostacyclin receptor agonists
tissular dual ERA
tyrosine kinase inhibitors
serotonin antagonists
TREATMENT
• EXPERIMENTAL COMPOUNDS
– earlier stage of development
•
•
•
•
•
•
rho-kinase inhibitors
vascular endothelial growth factor receptor inhibitors
angiopoietin-1 inhibitors
elastase inhibitors
Gene therapy
Stem cell therapy
TREATMENT
• COMBINATION THERAPY:
– standard of care but long-term safety and efficacy have
not been amply explored
– BREATHE-2 study: epoprostenol-bosentan
– STEP-1 study: iloprost – bosentan with marginal
improvement in 6MWT vs. iloporost after 12 weeks of
treatment
– TRIUMPH study: inhaled treprostinil +
bosentan/sildenafil: improvement of 6MWT only
– PACES study: epoprostenol + sildenafil : improvement
in 6 MWT and time to clinical worsening
– PHIRST study: tadalafil + bosentan: improved 6MWT
Humbert M et. al. Eur Respr J 2004
MacLaughlin V. et. al. Am J Respir Crit Care Med 2006
McLaughlin V et. al. Am J Respir Crit Care Med 2009
Simmoneau G et. al Ann Intern Med 2008
Galie N. et. al Circ 2009
TREATMENT
• TREATMENT OF ARRYTHMIAS
– atrial flutter and atrial fibrillation may occur
– restore stable sinus rhythm is associated with a
favourable long term outcome
– atrial fibrillation associated with a 2-year mortality of
>80%
Tongers J et. al
Am Heart J 2007
TREATMENT
• BALLOON ATRIAL SEPTOSTOMY
– inter-atrial communication (right to left shunting)
decompresses the right heart chambers and increases
the LV preload and cardiac output
– improves systemic O2 transport, and 6MWT
– decreases sympathetic hyperactivity
– graded balloon dilation and septostomy
– benefits WHO FC IV with right heart failure refractory to
medical therapy or severe syncopal symptoms; those
awaiting transplantation or when medical therapy is
unavailable
Sandoval J. et. al.
JACC 1998
TREATMENT
• BALLOON ATRIAL SEPTOSTOMY
– avoid in end stage patients with:
• baseline mean RA pressure of > 20 mmHg.
• O2 saturation at rest of <80% in room air
– should be on optimal medical therapy
• pre-conditioning with iv inotropes
– indications: severe IPAH, PAH associated with
surgically corrected CHD, CTD, Distal CTEPH,
PVOD, and pulmonary capillary hemangiomatosis
Kurzyna M. et. al
Chest 2007
TREATMENT
• TRANSPLANTATION:
– those who fail to improve on disease-specific
therapy and who remain in WHO FC III or IV
– heart-lung transplantation and double lung
transplantation (due to shortage of donors, double
lung is considered more)
– RV and LV systolic functions do not improve
immediately hemodynamic instability
Orens JB et. al.
J Heart Lung Transplant 2006
TREATMENT
• TRANSPLANTATION:
– single lung transplantation developing
complications  severe hypoxemia
– vast majority undergo bilateral lung transplantation
– overall 5-year survival 45-50% with evidence of good
quality of life
Trulock EP et. al
J Heart Lung Transplant 2006
SAS AND PAH
• prevalence of 27% of PAH in SAS (sleep apnea
syndrome)
• positive correlation with Body Weight, BMI, TSTSaO2 <90% (total sleep time spent at this O2sat),
PaCO2
• severity and duration of nocturnal desaturation
 remodelling and restructuring of the
pulmonary arteriolar walls permanent daytime
pulmonary HPN
Bady E. et. al. Thorax 2000
SAS AND PAH
• increased levels of ET-1 in patients with OSAS
compared to controls
• decreased with CPAP therapy
• vasoconstrictor and mitogenic effects of ET-1
contribute to the increased vascular risk in SAS
Phillips BG et. al. J. Hypertens 1999
Lerman A. et. al. Circ 1991