Pulmonary Arterial Hypertension: Bench to Bedside

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Pulmonary Arterial HypertensionBench to
Bedside

• DHMC Core Curriculum

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Disclosures

• Speakers Bureau
• Merck, Pfizer, Actelion, Encysive
• Consultant
• Actelion
• Encysive

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Cardiac Hemodynamics
22/ 6-10
120/80
6-10
0-5
20/ 0-5
120/10
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Cardiac Hemodynamics
Formulas

• Pulmonary vascular resistance
• High capacitance
• Low resistance
• Systemic vascular resistance
• Relatively fixed capacitance
• High resistance

Mean PA - PAOP
Cardiac Output
(12-7)/5 1 Wood Unit (80 resist)
(95 - 5)/5 18 Wood Units (1440
resist)
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WHO World Symposium, Venice 2003 PAH
Classification

• I. Pulmonary arterial hypertension
• Familial
• Idiopathic (formerly called primary)
• Related to
• Collagen-vascular disease
• Congenital heart disease, shunts
• Portal hypertension
• HIV infection
• Drugs / toxins/other
• Hemoglobinopathies (Sickle cell, thalassemia)
• Other
• II. PH related to pulmonary venous hypertension
  (left heart disease)
• III. PH related to disorders of respiratory
  system
• IV. PH caused by thromboemboli
• PE
• Non-thrombotic pulmonary embolism tumor,
  parasites
• V. Miscellaneous Sarcoid, extrinsic
  compression

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Helpful Studies

• ECG, CXR, ECHO
• Routine labs LFTs, ANA, HIV serology, CBC
• Pulmonary thromboemboli Perfusion lung scan, CT
  scan, pulmonary angio
• OSA sleep study

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Right Heart CatheterizationDiagnostic Gold
Standard

• RA and RV pressures
• Pulmonary artery pressure
• PAOP (capillary wedge pressure)
• Cardiac output
• Calculated pulmonary vascular resistance
• Prognostic (RAP, CI, mPAP)
• Response to vasodilator challenge

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Hemodynamics
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WHO 2003 Classification

• I. PULMONARY ARTERIAL HYPERTENSION (PAH)
• II. PULMONARY HYPERTENSION WITH LEFT HEART
  DISEASE
• III. PULMONARY HYPERTENSION ASSOCIATED WITH LUNG
  DISEASE AND/OR HYPOXEMIA
• IV. PULMONARY HYPERTENSION RESULTING FROM CHRONIC
  THROMBOTIC AND/OR EMBOLIC DISEASE
• V. MISCELLANEOUS

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Pulmonary Venous Hypertension

• Mitral valve disease
• Aortic valve disease
• Systemic hypertension
• Left ventricular dysfunction
• Systolic
• Diastolic
• Constrictive pericarditis
• Restrictive cardiomyopathies
• Diabetic cardiomyopathy

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Is It Left Heart Disease?

• Paroxsymal nocturnal dyspnea
• Orthopnea
• Atrial fibrillation
• Absence of right axis deviation
• Left atrial enlargement
• History of systemic hypertension, diabetes,
  coronary artery disease
• Obesity

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Case Presentation

• 70 yo man with tissue MVR in 2000
• Noted to have a mitral stenosis murmur on exam in
  2005 without symptoms.
• Echo 2005 Mild to moderate valve stenosis, PASP
  45mmHg
• Acute pulmonary edema in summer 2006.

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Transesophageal ECHO
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Hemodynamics
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Case Presentation

• 57 yo woman, treated for recurrent right heart
  failure
• PMH Morbid obesity, hypertension, diabetes
• Physical exam showed Wt 298 lbs, JVD, S4,
  accentuated P2, peripheral edema
• ECHO PASP 82, RV dilated, LVEF 60, normal
  mitral valve

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Hemodynamics
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WHO Classification

• I. PULMONARY ARTERIAL HYPERTENSION (PAH)
• II. PULMONARY HYPERTENSION WITH LEFT HEART
  DISEASE
• III. PULMONARY HYPERTENSION ASSOCIATED WITH LUNG
  DISEASE AND/OR HYPOXEMIA
• IV. PULMONARY HYPERTENSION RESULTING FROM CHRONIC
  THROMBOTIC AND/OR EMBOLIC DISEASE
• V. MISCELLANEOUS

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Lung/Respiratory Diseases Associated with PH
Obstructive Lung Diseases
Restrictive Lung Diseases

• Neuromuscular diseases
• Kyphoscoliosis
• Thoracoplasty
• Sequelae of pulmonary tuberculosis
• Sarcoidosis
• Pneumoconiosis
• Drug-related lung diseases
• Extrinsic allergic alveolitis
• Connective tissue diseases
• Idiopathic interstitial pulmonary fibrosis
• Interstitial pulmonary fibrosis of known origin

• COPD
• Asthma
• Cystic fibrosis
• Bronchiectasis
• Bronchiolitis obliterans

Respiratory Insufficiency of Central Origin

• Central alveolar hypoventilation
• Obesity-hypoventilation syndrome
• Obstructive sleep apnea

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Lung/Respiratory Diseases Associated with PH
Fibrosis
Emphysema
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COPD and Pulmonary Hypertension

• Retrospective study of 215 COPD patients
• 7.4 of patients with pulmonary hypertension out
  of proportion

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PAPm (mm Hg)
3
2
1
FEV1 ( pred.)
Thabut G et al. Chest. 20051271531-1536.
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WHO Classification

• I. PULMONARY ARTERIAL HYPERTENSION (PAH)
• II. PULMONARY HYPERTENSION WITH LEFT HEART
  DISEASE
• III. PULMONARY HYPERTENSION ASSOCIATED WITH LUNG
  DISEASE AND/OR HYPOXEMIA
• IV. PULMONARY HYPERTENSION RESULTING FROM CHRONIC
  THROMBOTIC AND/OR EMBOLIC DISEASE
• V. MISCELLANEOUS

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Case Presentation

• 24 yo man with a history of seizures, recent
  frontal lobe neurosurgery
• Developed sudden dyspnea and weakness two days
  before and again on the day of admission
• CT of chest showed a large pulmonary embolism in
  main PA

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Cath Lab
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Group I WHO PAH

• Idiopathic (formerly primary PAH)
• Familial (FPAH)
• Related to
• Connective tissue disease HIV infection
• Congenital heart disease Drugs and toxins
• Portal hypertension Other
• PAH with significant venule and/or capillary
  involvement
• Pulmonary veno-occlusive disease
• Pulmonary capillary hemangiomatosis

Proceedings of the 3rd World Symposium on
Pulmonary Arterial Hypertension. J Am Coll
Cardiol. 2004431S-90S.
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Pathophysiology of PAHAn Integrated View
Vascular Remodeling
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Schematic Progression of PAH
Pre-symptomatic/ Compensated
Symptomatic/ Decompensating
Declining/ Decompensated
CO
Symptom Threshold
PAP
Right Heart Dysfunction
PVR
Time
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Mediators and Pathways in PAH
Reduced Activity
Increased Activity
Prostacyclin Prostacyclin synthase Nitric
oxide Nitric oxide synthase VIP Kv
channel Fibrinolysis
Endothelin-1 Serotonin Thromboxane A2 Clotting
Factors Angiopoietin-1 PAI-1 Growth
factors Oxidant stress Inflammation
PAIplasminogen activator inhibitor
VIPvasoactive intestinal peptide.
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Humbert M, et al. NEJM. 2004.
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History of NR

• 63yo woman notes increasing dyspnea, particularly
  past 6 months, now O2 dependent
• Moderate COPD by PFTs, smoker
• RA, on immunosuppressives
• ECHO demonstrates RA/RV dilatation, 3 TR, PASP
  80 mmHg, septal flattening, normal LV

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Physical Exam

• WD, small frame, 63 yo woman, BP 120/70 P 90 R
  16, Wt. 119 lbs, O2 sat 99 on 2L nasal
• HEENT Moderate JVD
• Lungs Clear
• Cardiac exam Loud P2, TR murmur, RV lift.
• ABD unremarkable
• Ext 1-2 edema bilat

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Hemodynamics
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Targets for Current or Emerging Therapies in PAH
Humbert M et al. N Engl J Med. 20043511425-1436.
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FDA-Approved Therapies
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Epoprostenol

• Synthetic salt of prostacyclin
• Rapid efficacy short,3- to 5-min half-life
• Approved for Class III and IV
• Invasive requirescontinuous IV infusion
• Individualized dosingregimen required
• Two RCTs showing efficacy

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Long-term Outcome in IPAH With Epoprostenol
Survival
Cumulative Survival
Observed (n162)

IV Epoprostenol (n178)


PExpected
Historical Control(n135)
P0
6
12
18
24
30
36
0
12
24
36
48
60
72
84
96
108
120
Months
Months
No. at risk 178 129 85 57 36 21 7 3 1 IV
Epoprostenol 135 59 34 20 11 4 2 2 1 Historical
Control
McLaughlin VV et al. Circulation.
20021061477-1482. Sitbon O et al. J Am Coll
Cardiol. 200240780-788.
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Epoprostenol Side Effects

• Flushing
• Headache
• Diarrhea, nausea, vomiting
• Jaw pain
• Myalgia
• Hypotension
• Anxiety, nervousness, agitation
• Chest pain
• Dizziness

• Bradycardia
• Abdominal pain
• Dyspnea
• Back pain
• Sweating
• Dyspepsia
• Paresthesia
• Tachycardia
• Delivery site complications

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Treprostinil

• Longer-acting prostacyclin analogue (4-h
  half-life)
• Subcutaneous infusion recently approved for IV
  use
• Approved for Class II-IV
• Efficacy slower thanepoprostenol,
  requireshigher doses
• Site pain problematicwith subcutaneousinfusion

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Site Reaction to Treprostinil
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Iloprost

• Longer-acting prostacyclin analogue(20- to
  30-min half-life)
• Aerosolized delivery system
• Approved forClass III and IV
• Requires frequentinhalations (6-9x/d)

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Endothelin Receptor Antagonists
Nitric Oxide Pathway
Prostacyclin Pathway
Arginine
Arachidonic Acid
Nitric OxideSynthase
ProstacyclinSynthase
Prostacyclin
Nitric Oxide
ExogenousNitric Oxide
cGMP
cAMP
ProstacyclinDerivatives
ProstacyclinDerivatives
Phosphodiesterase Type-5
PhosphodiesteraseType-5 Inhibitors
VasodilatationandAntiproliferation
VasodilatationandAntiproliferation
Humbert M et al. N Engl J Med. 20043511425-1436.
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Bosentan

• Oral, dual (ETA and ETB) endothelin receptor
  antagonist
• Two RCTs showing efficacy
• Approved doses 62.5 mg bid starting dose for 4
  weeks increased to 125 mg bid maintenance dose
• Approved for Class III and IV

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Bosentan Prevented Significant Hemodynamic Decline

• Bosentan therapy significantly improved
  hemodynamics over 12 weeks
• Conventional therapy led to worsening
  hemodynamics over 12 weeks

191 dyn-sec-cm-5
0.5L/min/m2


5.1mm Hg
-1.6mm Hg


-223dyn-sec-cm-5

• 0.52L/min/m2

Treatment Effect 6.7 mm Hg
- 415 dyn-sec cm-5
1.02 L/min/m2
Adapted from Channick, et al. Lancet 2001.
significant change vs baseline
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Bosentan Safety

• Mild anemia may be induced
• LFT surveillance monthly
• Teratogencity may be an ERA class effect
• Ensure negative Pregnancy test before Rx
• Monthly thereafter
• Headaches, peripheral edema

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Phosphodiesterase Type-5 Inhibitors Mechanism
Humbert M et al. N Engl J Med. 20043511425-1436.
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Sildenafil Change from Baseline in 6MW Test
P


Mean change from baseline(m)
46 m
45 m
50 m
Week 4
Week 8
Week 12
Placebo (n65) Sildenafil 20 mg tid
(n65) Sildenafil 40 mg tid (n63) Sildenafil 80
mg tid (n65)
Galiè N et al for the Sildenafil Use in Pulmonary
Arterial Hypertension (SUPER) Study Group. N
Engl J Med. 200535321482157.
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Sildenafil Side Effects

• Nose bleed
• Headache
• Dyspepsia
• Flushing
• Insomnia
• Erythema
• Dyspnea exacerbated

• Rhinitis
• Diarrhea
• Myalgia
• Pyrexia
• Gastritis
• Sinusitis
• Paresthesia

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PAH Determinants of Risk
McLaughlin VV, McGoon MD. Circulation.
20061141417-1431.
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What is the Optimal Treatment Strategy?
Investigational Protocols
McLaughlin VV, McGoon MD. Circulation.
20061141417-1431.
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Investigational/New Therapies

• Ambrisentan
• Sitaxsentan
• Tadalafil
• Inhaled treprostinil
• Oral treprostinil
• Inhaled vasoactive intestinal peptide (VIP)
• Imatinib (PDGF-inhibitor)

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Combination Therapy for PAH Selection of Trial
Programs
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Final Caveats

• Comprehensive history and physical is foundation
  for diagnosis
• Noninvasive screening as indicated
• Treat any identified factor(s) that could
  contribute to or exacerbate pulmonary
  hypertension
• Invasive hemodynamics crucial
• Refer early

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The End