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Pulmonary Arterial Hypertension (PAH)

Group 1 (of 5) Pulmonary Hypertension characterized by hemodynamic and pathophysiologic

changes leading to an increased precapillary pulmonary arterial pressure at rest

WHO functional classes

o Class I: Pulmonary hypertension without limitations in physical activity (i.e., dyspnea,
fatigue, chest pain, near syncope)
o Class II: Pulmonary hypertension with slight limitation in physical activity
Comfortable at rest
Ordinary physical activity results in Sx (dyspnea, fatigue, chest pain, or near
o Class III: Pulmonary hypertension with limitation in physical activity
Comfortable at rest
Less than ordinary activity causes dyspnea, fatigue, chest pain, or near syncope
o Class IV: Pulmonary hypertension w/ inability to perform any physical activity without Sx
S/Sx of RHF
Dyspnea, fatigue, or syncope at rest

Epidemiology a/w Clinical classes

o Prevalence: ~12.4 cases per 1 million adults
o Idiopathic
MC affects patients 20-30 yo
Incidence: 5-10 per 1 million adults for idiopathic PAH
o Genetic mutations
TGF- family genes
BMPR2: 11-40% of Idiopathic PAH, 70% of heritable PAH
ALK-1, ENG, and SMAD9: 5%
o Drug or Toxin induced
Definite RF: aminorex, fenfluramine, dexfenfluramine, toxic rapeseed oil,

Likely RF: amphetamine, methamphetamine, L-tryptophan, dasatinib
Possible RF: Cocaine, Amphetamine-like drugs (i.e., phenylpropanolamine), St.
Johns wort, several ChemoThx agents, IFN- and IFN-

* Increased incidence of IFN-induced PAH in patients with multiple sclerosis

o Disease-associated
CHD Prevalence 5-10%
MC: Systemic sclerosis Prevalence 9%
Other: Mixed CT Dz, SLE, RA, Sjogren
Portal hypertension Prevalence 2-6%
HIV Prevalence 0.5%
Schistosomiasis mansoni
Autoimmune thyroid dz

Pathogenesis: Multifactorial
o Increased pulmonary vascular resistence occurs 2/2 vasocontriction, inflammation,
remodeling of the pulmonary artery wall via obstruction and proliferation, and
thrombosis, resulting in:
Abnormal function or expression of K+ channels in smooth mm. cells
Endothelial dysfunction
Impaired nitrous oxide and prostacycle production causes decreased

ability to vasodilate and prevent proliferation

Overexpression of TXA2 and Endothelin-1 causes excess vasoconstriction

and excess proliferation

o Increased VEGF and VEGF receptor expression results in increased vascular tone and
vascular remodeling

o Sx: dyspnea, fatigue, weakness, angina, near syncope or syncope, abdominal
distention, chest pain, edema, palpitations
Progressive SOB
Exertional chest pain may occur due to hypoperfusion during exertion
Exertional dizziness and/or syncope may develop 2/2 RV dysfxn
Late findings: peripheral edema and ascites
o Medication Hx: anorectics (aminorex, fenfluramine, dexfenlafurine, benfluorex),
rapeseed oil
o Social Hx: Amphetamine, methamphetamine and cocaine abuse
o Sexual Hx: HIV RF

Physical Exam
o Early dz: possibly unremarkable
o Lungs
Mostly normal
May find inspiratory crackles (indicative of ILD)
o CV
Parasternal lift at LUSB (pulmonary tap)
Significant pulmonic valve component of S2
TR (holosystolic murmur over the LLSB)
PR (early diastolic murmur at LUSB; Graham Steell murmur)
o Abdomen
Possible hepatomegaly and ascites in advanced dz
o Extremities
Signs of scleroderma: Telangiectasia, digital ulcers, sclerodactyly, calcinosis
Digital clubbing is typically not a/w PAH
Peripheral edema with cool extremities in advanced disease

o Suspect PAH in patients with unexplained exertional SOB without S/Sx of respiratory
disease or left heart disease
o Screening test: TEE (often Dx unexpectedly by TTE for a different indication)
Not suitable for ASx or mild PAH
Can determine probability based on Peak TRV (tricuspid regurgitation velocity)


> 3.4 m/s
2.9 3.4 m/s
2.9 3.4 m/s
2.8 m/s
2.8 m/s
Additional findings
RV to LV diameter ration > 1
Flattening of IVS


PV outflow (RVO) acceleration time < 105 ms

PR velocity > 2.2 ms
Pulmonary Aa diameter >25 mm
IVC diameter > 21 mm with decreased inspiratory collapse
RA area > 18 cm

o Confirmatory testing: Right heart catheterization (readings must be measured at rest)

Mean Pulmonary Aa P 25
Precapillary pulmonary hypertension (PCWP 15 with normal or reduced CO)
Absence of other causes of precapillary pulmonary HTN (i.e., pulmonary venoocclusive disease, pulmonary capillary hemangiomatosis, PH 2/2 lung diseases
and/or hypoxia, chronic thromboembolic PH)

o CXR: can assist in ruling out lung disease
Central pulmonary Aa dilatation
Pruning of peripheral blood vessels
Advanced disease may show RA and RV enlargement, with loss of retrosternal
airspace on lateral view 2/2 RV enlargement
o CT: consider for all PH
o V/Q scan: recommended for unexplained PH


o PFTs

Low PCO2 due to alveolar hyperventilation

Normal to slightly low PO2 at rest
DLCO may possibly be decreased (40-80% of predicted)
Mild to moderate reduction in lung volumes

o Supervised exercise rehabilitation in physically deconditioned patients with PAH
Low intensity exercise may increase peak O2 consumption in PAH
Structured exercise training may increase 6-minute walking distance in stable,
chronic PH

o Close observation for WHO Functional Class I

o Vasoreactivity testing
Can identify if patients specifically with idiopathic, heritable or drug-induced PAH,

can be treated using CCBs

Administer nitric oxide as a vasodilator (alternatives: IV epoprostenol, IV

adenosine, or inhaled iloprost)

Positive response: reduced mean Pulmonary Aa P 10 mm to reach an absolute

mean Pulmonary Aa P 40 mm with an increased or unchanged CO

Contraindications: Low systemic BP, Low CO, WHO Functional IV Sx

o CCBs: indicated for WHO Functional Classes II and III who have a positive response to
vasoreactivity testing; Start low, go slow
Initial doses
Slow release Nifedipine 30 mg BID
Diltiazem 60 mg TID
Amlodipine 2.5 mg QD
Increase cautiously and progressively to maximum tolerated dose
Nifedipine 120-240 mg per day
Diltiazem 240-720 mg per day
Amlodipine 20 mg per day
For relative bradycardia: nifedipine or amlodipine (peripheral DHP CCBs)
For relative tachycardia: diltiazem (central Non-DHP CCBs)
o If CCB are contraindicated OR Sx persist despite CCB Thx
WHO Functional Classes II III: Ambrisentan + Tadalafil
Prostanoids: WHO Functional Classes III and IV
Continuous IV Epoprostenal/Prostacycline/PGI2: may improve short-term

exercise capacity
Inhaled iloprost: May improve exercise capacity and functional status in

advanced disease
Subcutaneous trepostinil (remodulin): may improve exercise capacity
Oral treprostinil (orenitram) MonoThx: may improve walking distance
Endothelin receptor antagonists: WHO Functional Classes II, III, and IV
Bosentan, ambrisentan, macitentan
Improve exercise capacity and dyspnea; may improve functional class
Phosphodiesterase inhibitors: WHO Functional Classes II, III, and IV
Sildenafil, tadalafil, vardenafil
Improve exercise capacity
Soluble Guanylate Cyclase stimulators: WHO Functional Classes II and II

Riociguat: improve exercise capacity and delay clinical worsening of

disease in idiopathic, genetic and CT disease associated PAH

Combination Thx Ambrisentan + Tadalafil: WHO Functional Classes II and III
o Supportive Thx
Continuous long-term O2 Thx for PO2 > 60 mm
Oral anticoagulant, especially for idiopathic PAH (warfarin)
Diuretic (if S/Sx of RVF are present, i.e., fluid retention)
Avoid CV meds unless required by comorbidities (i.e., ACE , ARBs, BBs,
o Others:
Advise patients to avoid pregnancy
PPx: Influenza and Pneumococcal vaccines for
Supervised exercise rehabilitation in physically deconditioned PAH patients
o PAH patients require hospitalization in the ICU if:
HR > 110
SBP < 90
Low UO
Rising lactic acid
o Surgery
Balloon atrial septostomy
Lung transplant
o Follow-up appointments Q 3-6 months in stable PAH

SSRI use a/w decreased mortality among PAH patients

o RV Dysfxn/RHF
o Ascites
o Tachyarrhythmias (Afib and Aflutter)
o Comborbidities a/w increased mortality
DM2, COPD, CT Dz (especially systemic sclerosis)
o Biochemical markers associations
Increased serum uric acid a/w increased mortality
Decreased BNP a/w decreased mortality