Pulmonary Hypertension:
What you need to know
William Leeds, DO, FCCP
Pulmonary & Sleep Associates
Veritas Clinical Specialties
Topeka, KS
What is Pulmonary Hypertension?
• Definition
– Right heart
catheterization
showing
• Sustained
elevation of mean
pulmonary artery
pressure > 25
mmHg at rest
• Secondary RHC
parameters
– MPCWP < 15 mmHg
– PVR > 3 Woods
Units
WHO Classifications
• Group I: Pulmonary Arterial Hypertension
(estimated 15 cases per 1 million adults)
–
–
–
–
Idiopathic (primary)
Familial
Drug- and toxin-induced
Associated with connective tissue disease, HIV,
portal hypertension
– Associated with significant venous or capillary
involvement
– Persistent pulmonary hypertension of the
newborn
WHO Classifications, cont.
• Group II: Pulmonary Hypertension Owing
to Left Heart Disease
• Group III: Pulmonary Hypertension Owing
to Lung Diseases or Hypoxemia
• Group IV: Chronic Thromboembolic
Pulmonary Hypertension
• Group V: Pulmonary Hypertension with
Unclear Multifactorial Mechanisms
WHO Functional Classes of PAH
Class
Description
I
Patients with PH but without resulting limitation of
physical activity. Ordinary physical activity does not
cause undue dyspnea, chest pain, or near syncope.
II
Patients with PH 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.
III
Patients with PH 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.
IV
Patients with PH 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. Discomfort is increased by any
physical activity.
Pathogenesis of PAH:
Proliferative Vasculopathy
Triggers (Initiation Factors)
• Inflammation
• Autoimmunity
• Infection
• Hemodynamic shear stress
• Hypoxia
• Drugs/chemicals/toxins
Genetic Predisposition
• BMPR-2 and ALK-1 genes
• Kv channels
• Oxygen-sensing mechanisms
• 5-HHT
Activation Pathogenic
Vascular Mediators
• Endothelial dysfunction
– Vasoactive mediators
– Growth factors
Vascular Wall Remodeling
• Proliferation
• Vasoconstriction
• In-situ thrombosis
Adapted from Gaine S. JAMA. 2000;284:3160-3168.
Slide courtesy of Roxanna Sulica, MD.
Diagnosis of PAH
• Often made late in
the disease
– Median duration
between symptom
onset and diagnosis
is 27 months
• Late diagnosis due
to
– Under-recognition
– Nonspecific
symptoms
– Confusion with other
conditions
– iPAH is diagnosis of
exclusion
Signs and symptoms of PAH
• No early symptoms
• Progressive DOE,
fatigue, palpitations,
chest pains, cough,
hoarseness,
syncope
• Symptoms of RHF
– Ascites
– Edema
• Must screen highrisk populations
– Family history of
iPAH
– Connective tissue
disease
– Pulmonary
embolism
– Congenital heart
disease
Prognosis of iPAh is poor with
supportive care only
Median survival 2.8 years
Percentage surviving
100
80
60
40
20
0
0
0.5
1
1.5
2
2.5
3
Years of follow up
3.5
4
4.5
5
PAH/ssc progresses even more rapidly
Percent survival
100
80
No lung involvement
60
Lung involvement without PAH
40
20
PAH
0
0
1
2 3 4
5 6 7 8 9 10 11 12 13
Years from diagnosis of pulmonary hypertension
Diagnostic workup (CC: SOB)
• CXR
• Complete PFT
• Initial labs (CBC,
CMP, BNP)
• Physical exam
• Med hx/symptom
review
• Echocardiogram
• If echo shows PAH
– VQ scan/CT angio
– Labs (ANA, RF, HIV,
ANCA, anti-Scl 70,
ESR, CRP)
– Polysomnogram
– 6MWT
– RHC
Right heart catheterization
•
•
•
•
•
•
•
PA pressure
PCW pressure
Cardiac output
PA saturation
Pulmonary vascular resistance
Vasodilator challenge
Exercise challenge
Treatment options
• Treat the underlying/contributing
condition
• Oxygen if needed
– Check 6MWT and nocturnal oximetry
•
•
•
•
Oral medications
Inhaled medications
IV medications
Surgical interventions
Targets for PAH therapy
Oral medication options for PAH
• Warfarin (iPAH)
• Calcium channel blockers (amlodipine)
– Blocks entry of calcium into heart and muscle
cells
– Improves ability of heart to pump blood
– Relaxes smooth muscle in walls of heart and
smooth muscles
– Only a small number of PAH patients respond
– Side effects: nausea, h/a, rash, edema,
dizziness, fatigue
Oral medication options, cont.
• PDE-5 inhibitors
– Blocks the action of phosphodiesterase
– Dilates pulmonary vasculature
– Side effects: vision problems, h/a
• Endothelin receptor antagonists
– Blocks vasoconstrictive effects of
endothelin-1
– Dilates pulmonary vasculature
– Side effects: liver toxicity and anemia
(requires routine monitoring), edema
Inhaled medication options
• Inhaled iloprost (Ventavis)
– Dilates systemic and pulmonary vessels
– Inhaled multiple times daily
– Side effects: cough, h/a, throat pain
• Inhaled treprostinil (Tyvaso)
– Dilates systemic and pulmonary vessels
– Inhibits platelet aggregation
– Inhaled multiple times daily
– Side effects: cough, throat irritation, h/a
IV medication options
• IV epoprostenol (Flolan)
– Directly dilates peripheral vessels
– Inhibits platelet aggregation
– Must be initiated in hospital
– Cannot be stopped abruptly
– Side effects: h/a, nausea, jaw pain,
flushing, hypotension
Surgical options
• Atrial
septostomy
• Heart-lung
transplant
Treatment options summarized
Case Studies
• GL
• BB
• KS
Case Study GL
• Presented to
pulmonary service
in September 2006
at age 53
• Chief complaint was
progressive SOB
with exertion
• PMH: scleroderma
dx at age 39,
unspecified
arrhythmia, GERD,
depression,
allergies, arthritis,
and migraine h/a
• PSH: tonsillectomy
GL, continued
• Current
medications:
inderal, nexium,
miacalcin, percocet,
tramadol, mucinex,
alavert, vitamin C
• Allergies: imitrex
(unknown reaction)
• FH: COPD in
father, lung ca and
COPD in brothers
• SH: 30 pk-yrs of
cigarette use; quit in
2000
GL Diagnostics
• CXR 8/20/03: “mild decrease of lung
volumes and mild increased prominence of
interstitial markings in both lung bases since
1992 Some degree of interstitial lung
disease cannot be ruled out”
• PFT 9/19/06: FVC 2.19 L (70%), FEV1
1.79 L (70%), FEV1/FVC 82, IC 1.67 L
(77%), RV 1.15 L (64%), TLC 3.44 L (70%),
Diffusion 36%, DL/VA 2.53 L (55%)
GL Diagnostics, cont.
• Echocardiogram 8/21/06: EF 60-65%,
abnormal LV diastolic filling/impaired
relaxation, mild AR, mild MR, mild TR, mild
PR, RVSP 68 mmHg
• RHC 11/01/06: mean RA 10, mean RV 7,
PAP 70/29 (mean 44), MPCWP 13, CO ~4L;
adenosine trial showed decreased MPAP 38
• 6MWT: 390 m, O2 sat nadir 92% on room
air
GL Treatment Course
• November 2006: bosentan, sildenafil, and
warfarin initiated
• August 2007 CT: mild bibasilar interstitial
fibrosis
• October 2007: oxygen added
– 6MWT 183 m; O2 sat nadir 83% on room air
• November 2007: transtracheal oxygen
initiated
• February 2008: Ventavis added
GL Treatment Course, cont.
• August 2008: referred to KUMC
– RHC: normal EF, RA 8, MPAP 47, MPCWP 1214, CO 5.4
– 6MWT 428 m; O2 sat nadir 92% on 3L
– CT chest: progression of bibasilar fibrosis
– IV prostacyclin held due to stability of RHC
findings
• October 2008: unable to proceed with lung
transplant due to financial issues
• May 2009: 6MWT 292 m; O2 sat nadir 86% on 4L
GL Treatment Course, cont.
• June 2009:
– RHC: MPAP 66, MPCWP 22, CO 4.6
– Significant GERD symptoms
• February 2010: transitioned from Ventavis
to Tyvaso
• July 2010: symptoms acutely worsened
– Hospitalized for hemoptysis
– Hospice discussed
GL Treatment Course, cont.
• November 2010: last contact
– Echo: EF 65%, RV severely dilated with
moderate systolic dysfunction, RA
severely dilated, moderate TR, PAP 84
– PFT: FVC 1.83 (60%), FEV1 1.59 (65%),
FEV1/FVC 87, TLC 62%, Diffusion 11%
Deceased February 2011
GL Discussion
• Questions/comments?
Case Study BB
• Presented to
pulmonary service
in July 2002 at age
45
• Chief complaint was
progressive
dyspnea on exertion
for last 6 months
• PMH: poss. CVA or
seizure age 19 w/no
further recurrence
• PSH: none
• FH: CAD in father,
mother, brother
(brother had heart
surgery at age 46)
• SH: no tobacco or
illicit drug use
Case Study BB, cont.
• Current
medications:
Combivent inhaler
and previous use of
prednisone without
significant
improvement in
symptoms
• Allergies: NKDA
BB Diagnostics
• PFT 7/10/02: FVC 3.78 L (108%), FEV1
2.64 L (91%), TLC 6.18 l (114%), VC 3.78 L
(108%), RV 2.4 L (128%), Diffusion 94%
• ABG on room air 7/19/02: pH 7.395,
pCO2 36.8, PO2 57.1, BE -2.0, HCO3 21.9,
O2 sat 88%
• LHC 7/19/02: RA 1, RV 0, MPAP 50,
MPCWP 11, CO 4.21 L
• O2 sat 88% with ambulation
BB Treatment Course
• July 2002: Placed on Oxygen, digoxin
and bosentan
• Referred to Mayo Clinic, Rochester MN
– Diagnosed with Primary Pulmonary Htn
• September 2002: initiated on warfarin
• RHC 12/02: RA 7, MPAP 43, MPCWP 15,
CO 4.73; Flolan trial showed MPAP 46,
MPCWP 10, CO 7.43
– Amlodipine added
BB Treatment Course, cont.
• Echo 9/8/03: EF 63%, moderate RV
enlargement, moderately decreased RVSF,
RVSP 77
• Echo 11/04: RVSP 74, moderate RV
enlargement, mild TR
• Echo 02/06: severe RV enlargement,
RVSP 81
• February 2006: Sildenafil added
• Care turned over to Mayo Clinic physicians
• Last contact May 2006
BB Discussion
• Questions/comments?
Case Study KS
• Presented to
pulmonary service
August 2011 at age
46
• Chief complaint was
increased dyspnea
and LE edema x 2
months
• PMH: DVT/PE
1996, HTN, DM,
hypothyroid, obesity
and allergies
• PSH: none
• FH: father died age
48 of AMI; HTN, DM
• SH: works at a
bank, denies
cigarette and illicit
drug use
Case Study KS, cont.
• Current
medications:
amlodipine, vit E,
levothyroxine, MVI,
losartan/hctz, ASA,
furosemide, fish oil,
metformin, Ca/Vit D,
omeprazole,
warfarin, potassium
• Drug allergies:
NKDA
KS Diagnostics
• Labs 7/12/11: BNP 430, Hgb 11.1, Hct
34.6, BMP WNL, HIV neg.
• CT 7/22/11: no pulmonary emboli/no acute
process
• Cardiac stress test 7/27/11: LVEF 57%,
dilated RV, normal EKG
• Bilateral LE doppler 8/3/11: no DVT
• VQ lung scan 8/3/11: high probability for
PE in lateral segment of RLL
KS Diagnostics, cont.
• Echo 7/27/11: normal LVF, abnormal
septal motion likely r/t right-sided volume
overload, trace MR, RA and RV significantly
enlarged, mod TR, RVSP 107
• PSG 8/4/11: AHI 106, REM AHI 109,
baseline O2 sat 84%, O2 sat nadir 53%
KS Treatment Course
• August 2011: warfarin, nasal CPAP w/O2,
and weight loss initiated; CV meds adjusted
• October 2011: hospitalized for
dizziness secondary to abnormal
uterine bleeding (Hgb 6.2)
– Consideration given to IVC filter
• 098
Case Study CZ
• First presented to
pulmonary service
February 2010 at
age 66
• Chief complaint was
dyspnea, cough and
sputum production
• PMH: a-fib, chronic
bronchitis, HTN,
hypothyroid
• PSH: constrictive
pericarditis surgery
• FH: CAD in parents
• SH: 20 pk-yrs of
cigarette use, no
illicit drug use
Case Study CZ, cont.
• Current
medications:
Toprol, warfarin, vit
D, calcium, ASA,
furosemide,
levothyroxine,
albuterol, Benicar,
omeprazole,
simvastatin
• Allergies: cefdinir,
penicillin, codeine,
propoxyphene
CZ Diagnostics
• PFT 2/12/10: FVC 1.48 L (58%), FEV1 1.14 L
(59%), FEV1/FVC 77, TLC 5.03 L (110%), VC 2.53 L
(98%), RV 2.5 L, Diffusion 115%
• Echo 9/8/10: LV hypertrophy, EF 75%, moderate
RV enlargement with reduced RVSF, mod-severely
dilated RA, mild TR, RVSP 45-50
• RHC 9/8/10: MPCWP 31, MPAP 43, CO 2.7,
post-nitric oxide infusion CO 2.7