Pulmonary HTN

Dr. Micha kassirer, MD

”Dept. Internal medicine ”D
 Pulmonary
Hypertension
 Normal Pulmonary artery pressure at sea level:
Systolic 18-25
Diastolic 6-10
MPAP 12-16.

 Pulmonary Arterial Hypertension:

PASP >20
MPA > 25 (>35 with exercise)
and PAOP (PCWP) < 15 mm Hg.

 Prevalence of pulmonary vascular bed

decreases with age:
mild PH (MPA>20) 13% at age 45 and 28%
above age 75.
 Severity of Pulmonary
Hypertension

Degree of disease Mean PAP (mmHg)

Mild 25 - 40
Moderate 41 - 55
Severe >55
 Hemodynamic and clinical
squeal

 Increased pressure load on RV

 Significant variability exists on RVH/RV
dilatation
 Right ventricular failure is present when
an increased preload (RA pressure) is
required to maintain adequate cardiac
output
 Once RV failure is present, prognosis is
comparable to advanced CHF (NYHA
class III/IV)
 Pathophysiology
 Primary
 Secondary:
Hypoxic Vasoconstriction
Vasculature obliteration / lung
parenchyma
Volume overload – L → R shunt
Pressure overload – LV disease
Pulmonary Hypertension: Define Lesion
Post-Capillary PH
(PCWP>15 mmHg; PVR nl)

PAH
Respiratory Atrial Myxoma
Diseases Cor Triatriatum MV Disease
PE

VC RA RV PA PV LA LV Ao
PC
↑LVEDP
PV Systemic HTN
compression
PVOD AoV Disease

Pre-capillary Mixed PH Myocardial Disease

PH Dilated CMP-ischemic/non-isc.
PCWP<15 mmHg Hypertrophic CMP
Restrictive/infiltrative CMP
Obesity and others
Etiologic classification of pulmonary
hypertension

 FLOW = ΔP / PVR
 RVCO = MPAP - PCWP / PVR
 MPAP - PCWP = RVCO * PVR
 MPAP = CO * PVR + PCWP
 MPA = CO * PVR +

PCWP
Pulmonary venous
hypertension-most
common cause
 Usually due to left-
sided heart disease
(valvular, coronary or
myocardial), 
obstruction to blood
flow downstream
from the pulmonary
veins.
 Reversibility is
variable, dependent
on lesion, and
variable also in time
to regression--
 MPA = CO *PVR +
PCWP
 Hypoxia induced
pulmonary
vasoconstriction and
anatomical destruction
of the vascular bed due
to high pulmonary
resistance and
ultimately RV failure.
 The mechanisms of
pulm HTN are unclear--
include vasoconstriction
due to alveolar hypoxia
or neurohumoral
activation
 MPA = CO *PVR +
PCWP
 Chronic thrombotic and embolic
diseases
 Chronic thromboembolic disease*
 Tumor emboli
 Sickle Cell Disease**

 Pulmonary parenchymal disease

 Airway (emphysema, chronic bronchitis)
 Interstitial lung disease, pneumoconioses,
fibrosis
 Mechanism may be related to hypoxemia,
obliterative remodeling.
 MPA = CO *PVR +
PCWP
 Pulmonary vascular disease
 Collagen Vascular disease (SLE, P.nodosa, SS,
RA, polymyositis)
 Portal Hypertension
 HIV
 Toxins--anorexigens(Aminorex and fenfluramine),
cocaine and methamphetamines
 Pathologically indistinguishable from iPAH(PPH)
 Familial PAH
 Inflammatory diseases
 Sarcoidosis
 Schistosomiasis / Filariasis
 Pulmonary capillary hemangiomatosis
(microangiopathy/endothelial proliferation)
 MPA = CO *PVR +
PCWP
Pulmonary hypertension 
Acyanotic
due to left-to-right shunts
initially have high -ASD/VSD
.pulmonary blood flow -PDA
Over time this progresses- 
increased pulmonary Aortopulmonary septal defect
vascular resistance and Partial anomalous PV drainage
reversal of the shunt
((Eisenmenger complex Cyanotic
Increased pulmonary 
Total anomalous PV drainage
blood flow: beriberi,
*hyperthyroid, myeloma Single atrium
Okura, et al. High output heart failure as* Single ventricle
a cause of pulmonary hypertension.
Intern Med 33: 363, 1994 Persistent truncus
Transposition of great vessels
 CLINICAL SUBGROUPS
1. PULMONARY ARTERIAL HYPERTENSION
Idiopathic, Familial, Related to CVD, CHD, HIV, drugs, toxins, other

 PULMONARY HYPERTENSION WITH LEFT HD

Atrial or ventricular heart disease, Valvular heart disease

3. PH WITH LUNG DISEASE AND HYPOXEMIA

COPD, ILD, OSAHS, other

4. PH D/T THROMBEMBOLIC DISEASE

5. MISCELLANEAOUS
Sarcoidosis, hystiocytosis, pulmonary vessels compression
 Clinical Evaluation of PAH
 Symptoms:
Insidious onset of shortness of
breath
 Often results in delayed diagnosis
Chest pain
Fatigue
Syncope/presyncope with exertion
Peripheral edema or ascites
Raynaud’s in about 10% (worse
prognosis)
Hemoptysis (rare)
 Physical Findings in
Pulm HTN
 clear lungs
 Cor pulmonale: hepatomegaly,
pulsatile liver, ascites, peripheral
edema
 no clubbing (if present implicates
CHD)
 hoarseness of voice (Ortner
syndrome)
 stigmata of secondary causes of
PAH:
 Physical Findings in
Pulm HTN
 Accentuated P2
 Wide of fixed S2 splitting
 Right ventricular S4, S3
 RV heave along left sternal border
 Elevated JVP, with Large A waves
from stiff RV
 Systolic murmur of TR
 Assessment of Disease
Severity
 History, History, History
 Etiology
 Effort tolerance
 6 minute walk
 Hemodynamics (Pressure and Flow)
 PAM, CO, and RA (right heart failure)
 Response to acute vasodilator challenge
 Inhaled NO
 IV prostacyclin
 IV adenosine
 IPAH/FPAH
Epidemiology and Natural History
Predictors of Prognosis

NYHA Class Median Survival

I and II 5 years
III 2.5 years
IV 6 months

5-year survival: 27% NYHA Class III/IV

 Predictors of Poor Prognosis

 Poor exercise capacity (6 MWD)

 Cardiopulmonary hemodynamics
 High right atrial pressure
 Low cardiac index
 High mean pulmonary artery pressure
 Enlarged right atrium on echo
 Pericardial effusion on echo
 Absence of anticoagulant use
 Absence of initial acute vasodilator response
 Laboratory work-up
 History, History, History…..
 ABG
 Collagen vascular disease screen
 HIV
 Coagulation studies (esp. D-dimer)
 Pulmonary Function test
 Imaging: CXR, CT-angio, HRCT
 Cardiac evaluation: TTE + contrast / TEE
 Rt. Heart catheterization
 CHEST X-Ray

Clear lung fields Interstitial markings

Pulmonary Consider parenchymal

function tests lung disease or
venoocclusive disease

Obstructive Restrictive
pattern Normal pattern
pattern

Secondary to Possible Possible interstitial lung

COPD PAH disease

Arterial Blood Gases

Normocapnea hypercapnea
or hypocapnea

Consider
hypoventilation
Perfusion lung scan syndrome

Segmental or Normal or patchy

non-segmental Echocardiogram
larger defects
defects

Pulmonary angiogram Normal

Thromboembolic Without primary primary cardiac

disease cardiac disease disease

Cardiac Catheterization
 Rt. And Lt. Heart
catheterization

• O2 Step-up in R.A.
• Qp/Qs 84%

• Wedge pressure
• Acute vaso-reactive testing
•Coronary angiography
•
Idiopathic Pulmonary Fibrosis: Significance of PAH

Lettieri, et al Chest 2006

Eisenmenger’s Syndrome
 PAM = PVR*CO (PBF) + PWP
 If PBF is doubled, a proportionate (half)
reduction in PVR maintains PAM
 If PBF increased, the reserve capacity of
pulmonary vascular elastance is exceeded
 rise in PAM pulmonary hypertension
 Higher PBFhigher PVR in post-tricuspid
shunting (VSD, PDA)higher PA pressures
shunt reversal (balanced or RL)
 Reversibility of Pulmonary
Vascular Disease in CHD
 Extent of reversibility of obstructive
vascular disease varies after correction of
hyperkinetic lesion
 Reversible: Medial hypertrophy and
vasoconstriction
 Irreversible: Plexiform lesions and
necrotizing arteritis
 High risk/benefit for surgical closure:
 PVR>SVR and high grade arteriopathy present
 Prohibitively high risk when balanced or RL
shunts present, when high RA pressures or RV
failure present
 At-Risk Populations for
PAH
Populations Prevalence/Incidence

IPAH1 million/1-2

CTD2
Systemic Sclerosis 30%
CREST syndrome 50%
UNCOVER3 (newly identified 11%) 27%
Up to 50% of patients with large VSDs develop
CHD4
Eisenmenger syndrome, often associated with PAH

HIV5 1/200

SCD6 20-40%

Direct relationship with anorexigens (amphetamines,

Drugs/Toxins7
cocaine); L-tryptophan may also be associated with PAH

1
Rich et al. CHEST 1989; 2 Braunwald et al. Heart Disease, 6th ed.; 3 Wigley et al. Arth Rheum 2005
4
Simmoneau et al. JACC 2004; 5 Speich et al. CHEST 1991; 6 Lin et al. Curr Hematol Rep 2005. 7 Rich et al. CHEST 2000.
 Pathogenesis of Pulmonary Arterial
Hypertension

IRREVERSIBLE
NORMAL REVERSIBLE DISEASE DISEASE
PAH: Pathophysiology

Dilated RV- Intact pericardium

↑ RAP
⇓
↑ Intrapericardial pressure (IPP)
⇓
↓ LV transmural filling pressure=
LVEDP-IPP
+
Shift of IV septum toward LV
⇓
↓ LV preload and ↓ LV
distensibility
⇓
↓↓ Systemic Cardiac Output
 IPAH/FPAH
Epidemiology and Natural History
Predictors of Prognosis

NYHA Class Median Survival

I and II 5 years
III 2.5 years
IV 6 months

5-year survival: 27% NYHA Class III/IV

 Predictors of Poor Prognosis

 Poor exercise capacity (6 MWD)

 Cardiopulmonary hemodynamics
 High right atrial pressure
 Low cardiac index
 High mean pulmonary artery pressure
 Enlarged right atrium on echo
 Pericardial effusion on echo
 Absence of anticoagulant use
 Absence of initial acute vasodilator response
 IPAH/FPAH (PPH): Progressive disorder
associated with high mortality rate
PAH Survival-NIH registry data 1980’s
100
Time from sx to dx: 2.5 yrs
Percentage Surviving

Median: 2.8 yrs

80
50% survival at 2.5 yrs

60
68%
40
48%
50% mortality at 2.5 years
if left untreated 34%
20

0
0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5
Years of Followup

Adapted from: D’Alonzo GE, Barst RJ, Ayres SM. Survival in patients with PPH: Results from a
National Prospective Registry. Ann Internal Med. 1991; 115: 343-349
 Goals of Therapy

 Alleviate symptoms, improve exercise

capacity and quality of life
 Improve cardiopulmonary
hemodynamics and prevent right
heart failure
 Delay time to clinical worsening
 Reduce morbidity and mortality
 PAH Therapy: Life style
considerations
 Sodium restriction
 Abstinence from smoking
 Avoid high altitude
 <4,000 feet above sea level
 Avoid physical exertion in setting of
pre- or frank syncope sx
 Avoid pregnancy
 PAH: Therapy
 Pharmacologic
 Vasodilators/Vasoremodeling therapy (CCB, oral bosentan,
inhaled iloprost; SQ/IV treprostinil; IV epoprostenol, oral sildenafil)
 Supplemental O2
 Anticoagulation (INR≈ 2-3)
 Diuretics (↓excessive preload)
Rx for RV
}
 Digoxin
 IV inotropes (low dose dobutamine, failure
dopamine 1-2 mcg/kg/min)
 Algorithm for Assessment of
Vasoreactivity in Patients with PAH
Right Heart Catheterization With
Acute Vasoreactivity Testing
(iNO, epoprostenol, adenosine)
mPA ↓10 mmHg
↓ mPA < 40 mmHg

Non - responder Responder (<15%) and

candidate for CCB (no RHF)

Consider p.o. Bosentan

Consider p.o. Sildenafil
Consider Inhaled Iloprost
Consider s.q. Treprostinil
Consider Continuously-Infused
Epoprostenol
Hemodynamically-Monitored Trial of
Calcium Channel Blocker
Therapy
 Strategies to Prevent and Treat
Right Heart Failure
 Reduce RV wall stress (↓MVO2, ↓ischemia)
 Reduce RV afterload
 Pulmonary vasodilators (O2, CCB, ERA’s, prostanoids, nitric
oxide)
 Anticoagulation to prevent thrombosis
 Reduce RV preload and TR
(diuretics: loop, aldosterone antagonists)
 Improve RV inotropy
 Chronically: digoxin
 Acutely:
• IV epoprostenol, IV treprostinil
• low dose IV dobutamine or dopamine
 Invasive Treatment of Advanced
RV Failure

 Atrial septostomy +/- ECMO

 Improve LV filling and systemic C.O
 Surgical Therapy

 Transplantation - lung / heart-lung

 Reserved for patients who continue to
deteriorate with poor QOL despite aggressive
pharmacologic therapy
1 year survival - 65-70%
5 year survival - 40-50%
 PAH: Randomized Control Trials of
Approved Agents

/Study N PositiveResul
Class of Drug Drug Etiol Design ts Dis-advantages
*Class

MWD 6
ET-1 BREATHE-1 213 -Double Symptoms Hepatic toxicity
Antagonist / OralBosentan PAH Blind Clinical ;(11%
placebo III,IV wk-16 Worsening (transient, reversible
CPH

SUPER 278 Double- MWD 6

PDE-5 Inhibitor Sildenafil Citrate IPAH,CT blind, CPH Headache, flushing,
,(20 CHD placebo Symptoms dyspepsia
(or 80 mg tid 40 II, III wks 12

Prostacyclin Inhalational 203 Double- Composite Administration

analogue /Iloprost PH blind Endpoint to 9 times daily 6
Placebo III-IV week-12 MWD, sx 6

Prostacyclin / SQTreprostinil 470 Double- MWD 6 Pain, erythema

analogue SQ placebo PAH blind Symptoms at infusion site
II-IV wk-12 CPH Side effects

MWD 6 Indwelling central

/ IVEpoprostenol 81 -Open Symptoms line
Prostacyclin Conventional Rx PPH Label CPH Pump
III,IV wk-12 Survival (infection,malf)
Side effects
 Targets for Therapy in
PAH

Humbert et al. New Engl J Med 2004

 Endothelin isincreased in
IPAH and PAH associated
with other Diseases
Congenital
IPAH Scleroderma
Heart Disease
P<0.001 P<0.05 5 P<0.001

Delta ET-LI (PV-RV) (pg/ml)

10 Concentration of ET-1(pg/ml) 10
4
8
IrET-1 (pg/ml)

8 3
6
4 2
6
2 1
0 4 0
Non-PPH PPH LcSSc LcSSc Non-PH PH
Non-PAH PAH

Stewart et al., Ann Inter Med,1991 Vancheeswaran et al., J. Rheum, 1994 Yoshibayashi et al., Circulation, 1991
 Endothelin is a Key
*Pathogenic Mediator
Proliferation Vasoconstriction
 Vascular Smooth Muscle
 Fibroblasts  Direct Or Via Facilitation Of
Other
 Vasoconstrictor Systems (Renin
 Angiotensin System,
Hypertrophy ET Sympathetic)
 Cardiac/Vascular

Fibrosis
 Fibroblast Proliferation
  Extracellular Matrix Proteins
 ↓ Collagenase Production
Inflammation
  Vascular Permeability
 Neutrophil / Mast Cell Activation
 Promotes Cellular Adhesion
  Cytokine Production

*Based on observations reported from in-vitro, in-vivo, or animal models. The

clinical significance in humans is unknown.
Clozel. Ann Med. 2003
 BREATHE-1: 6-Minute Walk Test
Change From Baseline at Week 16

60 Placebo (n = 69) Bosentan (n = 144)

∆ Walk Distance

40
(meters)

20 P = 0.0002 Mean ± SEM

-20

-40
Baseline Week 4 Week 8 Week 16

62.5 mg bid 125 or 250 mg bid

Rubin L et al. NEJM 2002

 BREATHE-1:Time to Clinical
*Worsening
100 95%
89%
Event-Free (%)

p = 0.0038 75% p = 0.0015

75
63%

50

25 Bosentan (n = 144) Bosentan (n = 35)

Placebo (n = 69) Placebo (n = 13)

0
0 4 8 12 16 20 24 28
Time (weeks)
* Time to clinical worsening = Shortest time to either death, premature withdrawal or
hospitalization due to PHT worsening, or initiation of epoprostenol therapy
BREATHE-1 Trial: Bosentan in PAH
Recommended Laboratory
Monitoring with Bosentan
• Liver function testing
 Prior to initiation of treatment
 Monthly

• Hemoglobin
 Prior to initiation of treatment
 After 1 month, then every 3 months

• HCG
 Prior to initiation of treatment
 Monthly
Phosphodiesterase-5
)inhibitors )PDE5-I
Baseline Characteristics: Sildenafil Trial
Sildenafil: Outcomes
PROSTENOIDS
 Recently Approved Therapy
Inhalational Iloprost (Ventavis®)
Approved for WHO Class III, IV patients
with PAH
Properties:
 Selective pulmonary vasodilator
 Vasodilatory potency similar to PGI2
 Exerts preferential vasodilation in well-
ventilated lung regions
 Longer duration of vasodilation than
PGI2 (30-90 vs 15 min)
 Ventavis® (iloprost) Inhalation
Solution :
Dosage and Administration
 Indicated for inhalation via the Prodose® AAD® system only
 2.5 mcg initial dose
 increase to 5 mcg if 2.5 mcg dose is tolerated
 maintain at maximum tolerable dose (2.5 mcg or 5 mcg)
 6-9 inhalations daily during waking hours; 8-10 minutes each
 Inhalational Iloprost (AIR)
Olschewski et al, NEJM 2002, 347:322-9
Inhaled Placebo
N=203
NYHA III or IV
PAH, CTPH 2.5 or 5.0 ug (6 or 9 x/d, median 30ug/d)

Inhaled Iloprost

Baseline 12 weeks

ILOPROST Results:
1o End-point
10% ↑6-min walk
Primary endpoint met (17% vs 5%;p=0.007) & improved NYHA Class
6-min walk distance improved (36 m, p=0.004) w/o clinical deterioration
NYHA class improved (p=0.03) or death
Dyspnea improved (p=0.015)
Minimal improvement in cardiopulmonary hemodynamics
Subcutaneous Treprostinil
( (Remodulin


•SQ administration
•Longer half-life than epoprostenol
•Pre-mixed
•Stable at room temperature
 FLOLAN
 Sodium epoprostenol (Flolan)--short-
lived relatively locally acting
vasodilator, t1/2 3-5 minutes.
 Most potent effect --⇑ cardiac output in
patients with PAH
 ⇓Resting heart rate, ⇓mean right atrial
pressure, and a marked improvement in
survival.
 Abrupt cessation can be fatal
 Contraindicated in veno-occlusive
disease
IV epoprostenol (flolan)
 PPH Study
N=81 Randomization
NYHA Class III or IV
Epoprostenol +
Conventional Therapy

Baseline
Screening
Dose
Ranging Conventional Therapy

12 weeks
Epoprostenol Improved:
• Exercise Capacity
mean rx effect 47 m, p<0.003
• Cardiopulmonary Hemodynamics
rx effect: PA m ≈ 7 mmHg CI ≈ 0.5 L/m/m2
PVR ≈ 6 Wu
• Dyspnea
• NYHA Class
• Survival Barst RJ et al. NEJM, 334: 296-301, 1996.
Barst RJ et al. NEJM, 334: 296-301, 1996.
 PAH: Therapy
( Epoprostenol (Flolan
 Adverse effects 2˚ delivery system
 Pump malfunction
 Catheter related infections
 Thrombosis
 Drug-induced side effects
 Flushing, headache, jaw pain, diarrhea, nausea,
myalgias, arthralgias
 Thrombocytopenia
 Tolerance
 Cost
 Outpatient cost up to $100,000 per year
 Conclusion
 Pulmonary arterial hypertension is a progressive
disease with significant morbidity and mortality
 Right heart failure is an important development
which clearly prognosticates and marks disease
progression
 Treatment of right heart failure is essential
 Therapies with proven benefit in transpulmonary
hemodynamics, functional class and exercise
tolerance include ET-1 receptor antagonism
(bosentan), prostanoids, and oral sildenafil.
 Continuous IV Flolan is reserved for advanced
(class IV) disease where there is a proven survival
benefit