The%20Basics%20of%20Pulmonary%20Hypertension

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The Basics of Pulmonary Hypertension

• Lana Melendres-Groves
• Assistant Professor of Medicine
• Director, Adult Pulmonary Hypertension Program
• Division Pulmonary Critical Care Medicine
• UNMHSC

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Objectives

• Definition of PH/PAH and pathophysiology
• WHO groups
• Natural history of PAH
• Clinical presentation/PE/studies
• Timing and type of work-up
• Who gets therapy
• Monitoring of therapy

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Case 1

• 27yo woman with PMHx significant for exercise
  induced asthma and anxiety presenting to the ED
  after almost passing out.
• She has a 10mnth old daughter and felt that maybe
  she just hadnt gotten into shape after having
  the baby.
• SOB when she tries to jog or walk up her stairs.

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Case 2

• 29yo man with HIV presenting to the ED with 2
  month h/o of worsening SOB on exertion that has
  dramatically worsened over the past week to the
  point that he is now having SOB at rest and
  feeling dizzy when standing not on any
  medications.
• Recently moved from California and has no
  information in our system.

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Case 3

• 42yo obese woman who doesnt like doctors that
  presented after she had worsening fatigue and sob
  with minimal activity.
• She is a hairdresser and overall is upset that
  she is overweight so never steps on a scale.
• She doesnt take any medications.
• Has noticed swelling in her legs.
• TTE shows severe RV enlargement and PASP of
  95mmHg with rt to left shunt seen.

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Case 4

• 65yo woman with little PMHx presenting with SOB
  and exhaustion. Has no medical problems that she
  knows of, just retired from teaching for the past
  40years in California and relocated to Ruidoso,
  NM.
• Previously playing 18 holes of golf, now only
  able to walk 15ft before needing to stop and
  rest.
• Massive LEE and decreased mobility of her hands.

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Case 5

• 83yo woman has been healthy her whole life now
  presenting with worsening fatigue with exertion.
• Previously able to swim for 30 minutes a day and
  walk for 30min, now sob with much less. Unable to
  keep up with her friend.
• Experiencing palpitations and chest pressure
  intermittently.
• TTE shows mild RA and RV enlargement with a PASP
  of 55mmHg

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Case 6

• 52yo man with ESRD on HD, htn, DM, CAD, cirrhosis
  from hep C and prior ETOH abuse and mild COPD, no
  longer smoking, admitted after missing two HD
  appointments with profound fluid overload.
• Also notes that he has had worsening SOB over the
  past year and fluid retention.

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Normal Cardiac Hemodynamics
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Diagnostic Definition Pulmonary Hypertension

• Rest
• - Mean PAP gt25 mmHg
• PAH above PCWP or LVEDP lt15 mmHg
• PVR gt3 WU
• Associated with adverse changes
• - In the pulmonary vasculature (arteriopathy)
• - At the level of the right ventricle
  (hypertrophy)
• No longer part of the definition
• Exercise
• - Mean PAP gt 30 mmHg

Gaine et al. The Lancet, 1998.
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Aberrant Pathways in PAH
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Loss of Biological Balance in PAH
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The Pathobiology Of Pulmonary Hypertension
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5th World Symposium Classification of Pulmonary
Hypertension (Nice, France 2013)

• 1. Pulmonary Arterial Hypertension
• 1.1 Idiopathic PAH
• 1.2 Heritable
• 1.2.1. BMPR2
• 1.2.2. ALK1, ENG, SMAD9, CAV1, KCNK3
• 1.2.3 Unknown.
• 1.3 Drug- and toxin-induced
• 1.4 Associated with
• 1.4.1. Connective tissue disease
• 1.4.2 HIV infection
• 1.4.3 Portal hypertension
• 1.4.4 Congenital heart diseases
• 1.4.5 Schistosomiasis
• 1 Pulmonary veno-occlusive disease (PVO)
  and/or pulmonary capillary hemangiomatosis (PCH)
  
• 1 Persistent pulm hypertension of the newborn
  (PPHN)
• 2. Pulmonary hypertension due to left heart
  disease
• 2.1 LV Systolic dysfunction
• 2.2 LV Diastolic dysfunction

• 3. Pulmonary hypertension due to lung diseases
  and/or hypoxia
• 3.1 Chronic obstructive pulmonary disease
• 3.2 Interstitial lung disease
• 3.3 Other pulmonary diseases with mixed
  restrictive and obstructive pattern
• 3.4 Sleep-disordered breathing
• 3.5 Alveolar hypoventilation disorders
• 3.6 Chronic exposure to high altitude
• 3.7 Developmental lung disease
• 4. Chronic thromboembolic pulmonary
  hypertension (CTEPH)
• 5. PH with unclear multifactorial mechanisms
• 5.1 Hematologic disorders chronic hemolytic
  anemia myeloproliferative disorders splenectomy.
• 5.2 Systemic disorders, sarcoidosis,
  pulmonary Langerhans cell histiocytosis,
  lymphangioleiomyomatosis, neurofibromatosis,
  vasculitis
• 5.3 Metabolic disorders glycogen storage
  disease, Gaucher disease, thyroid disorders
• 5.4 Others tumoral obstruction, fibrosing
  mediastinitis, chronic renal failure on
  dialysis.

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Back to the Cases

• What do all the patients presented have in
  common?
• Each patient was found to have pulmonary arterial
  hypertension after full w/u and diagnosis by
  right heart catheterization.

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Pulmonary Arterial Hypertension

• Case 1 IPAH
• Case 2 PAH associated with HIV

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PAH

• Case 3 PAH assoc with drugs/toxins
• - The list gets longer and
• longer
• Case 4 PAH assoc with CTD
• - Sometimes the PH presents
• before other complications
• of the disease

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Drugs and Toxins Associated PAH

• Definite

• Possible

• Aminorex
• Fenfluramine
• Dexfenfluramine
• Toxic rapeseed oil
• Benfluorex
• SSRIs
• Likely
• Amphetamines
• L-tryptophan
• Methamphetamines
• Dasatinib

• Cocaine
• Phenylpropanolamine
• St Johns Wort
• Chemotherapeutic agents
• Interferon alpha/beta
• Amphetamine-like drugs
• Unlikely
• Oral contraceptives
• Estrogen
• Cigarette smoking

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PAH

• Case 5 PAH assoc with CHD
• Case 6 PAH assoc with portal htn

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Hemodynamic Classification of PH(mean PAP gt25 mm
Hg)
Post-capillary PH
LV
PV
RA
RV
PA
LA
Ao
VC
PC
Mixed PH
High-flow PH (O2 sat run)
Pre-capillary PH
Diagram courtesy of Teresa De Marco, MD, UCSF
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Hemodynamic Classification of PH(mean PAP gt25 mm
Hg)
Post-capillary PH PCWPgt15 mm Hg PVR normal
RA
RV
PA
PV ?PVP
Ao
LA ?LAP
VC
LV
PC
?LVEDP
Diagram courtesy of Teresa De Marco, MD
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Hemodynamic Classification of PH(mean PAP gt25 mm
Hg)
Post-capillary PH PCWPgt15 mm Hg PVR normal
MR
RA
RV
PA
PV ?PVP
Ao
LA ?LAP
VC
LV
PC
?LVEDP
Systemic HTN AoV disease
Myocardial Disease Dilated CMP-ischemic/non-ischem
ic Hypertrophic CMP Restrictive/infiltrative
CMP Obesity related CMP Pericardial disease
Diagram courtesy of Teresa De Marco, MD
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Hemodynamic Classification of PH(mean PAP gt25 mm
Hg)
Post-capillary PH PCWPgt15 mm Hg PVR normal
RA
RV
PA
PV ?PVP
Ao
LA
VC
LV
PC
PV Compression
Diagram courtesy of Teresa De Marco, MD
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Hemodynamic Classification of PH(mean PAP gt25 mm
Hg)
PAH Lung diseases /- hypoxemia CTEPH

LV
RA
RV
PA
PV
LA
Ao
VC
PC

Pre-capillary PH PCWP lt15 mm Hg PVR gt3 woods
units
Diagram courtesy of Teresa De Marco, MD
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5th World Symposium Classification of Pulmonary
Hypertension (Nice, France 2013)

• 1. Pulmonary Arterial Hypertension
• 1.1 Idiopathic PAH
• 1.2 Heritable
• 1.2.1. BMPR2
• 1.2.2. ALK1, ENG, SMAD9, CAV1, KCNK3
• 1.2.3 Unknown.
• 1.3 Drug- and toxin-induced
• 1.4 Associated with
• 1.4.1. Connective tissue disease
• 1.4.2 HIV infection
• 1.4.3 Portal hypertension
• 1.4.4 Congenital heart diseases
• 1.4.5 Schistosomiasis
• 1 Pulmonary veno-occlusive disease (PVO)
  and/or pulmonary capillary hemangiomatosis (PCH)
  
• 1 Persistent pulm hypertension of the newborn
  (PPHN)
• 2. Pulmonary hypertension due to left heart
  disease
• 2.1 LV Systolic dysfunction
• 2.2 LV Diastolic dysfunction

• 3. Pulmonary hypertension due to lung diseases
  and/or hypoxia
• 3.1 Chronic obstructive pulmonary disease
• 3.2 Interstitial lung disease
• 3.3 Other pulmonary diseases with mixed
  restrictive and obstructive pattern
• 3.4 Sleep-disordered breathing
• 3.5 Alveolar hypoventilation disorders
• 3.6 Chronic exposure to high altitude
• 3.7 Developmental lung disease
• 4. Chronic thromboembolic pulmonary
  hypertension (CTEPH)
• 5. PH with unclear multifactorial mechanisms
• 5.1 Hematologic disorders chronic hemolytic
  anemia myeloproliferative disorders splenectomy.
• 5.2 Systemic disorders, sarcoidosis,
  pulmonary Langerhans cell histiocytosis,
  lymphangioleiomyomatosis, neurofibromatosis,
  vasculitis
• 5.3 Metabolic disorders glycogen storage
  disease, Gaucher disease, thyroid disorders
• 5.4 Others tumoral obstruction, fibrosing
  mediastinitis, chronic renal failure on
  dialysis.

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Natural History of PAH NIH Registry1,2
Percent survival
Predicted survival
Predicted survival
Years
NIH National Institutes of Health.Predicted
survival according to the NIH equation. Predicted
survival rates were 69, 56, 46, and 38 at 1,
2, 3, and 4 years, respectively. The numbers of
patients at risk were 231, 149, 82, and 10 at 1,
2, 3, and 4 years, respectively. Patients with
primary pulmonary hypertension, now referred to
as idiopathic pulmonary hypertension. 1. Rich et
al. Ann Intern Med. 1987107216-223. 2. DAlonzo
et al. Ann Intern Med. 1991115343-349.
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Survival by PAH Etiology
Prognosis in Mixed Treated/Untreated Cohorts
Percent survival
Years
CHD congenital heart disease CVD collagen
vascular disease HIV human immunodeficiency
virus PAH pulmonary arterial hypertension PPH
primary pulmonary hypertension PoPH
portopulmonary hypertension.
McLaughlin et al. Chest. 200412678S-92S
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Symptoms

• Breathlessness
• Chest pain
• Dizziness
• Syncope
• Loss of energy
• Edema
• Dry cough
• Raynauds phenomenon

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Physical Exam Findings in PAH

• Increased jugular venous pressure
• Accentuated split S2
• Presence S3
• TR murmur- heard best LL sternal border
• Edema and/or ascites
• Hepatojugular reflux
• Skin- telangiectasias, Raynauds, Sclerodactyly

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CXR
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CT Chest
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Pulmonary Arterial Hypertension Detection and
Diagnosis
Is there a reason to suspect PAH Clinical history
(symptoms, risk factors, family Hs.), Exam, CXR,
ECG
yes
no
Rationale
Is PAH likely? Echo
TRV to measure RVSP RVE RAE RV Dysfunction
No further evaluation for PAH
no
yes
yes
Is PAH due to LH disease? Echo
Dx LV systolic, diastolic dysfunction valvular
disease Appropriate treatment and further
evaluation if necessary, including RLHC
no
Dx abnormal morphology shunt Surgery. Medical
treatment of PAH or evaluation for further
definition or other contributing causes,
including RLHC if necessary
yes
Is PAH due to CHD? Echo with contrast
no
Dx Scleroderma, SLE, other CTD, HIV
Medical treatment of PAH and further evaluation
for other contributing causes, including RHC
yes
Is PAH due to CTD, HIV? Serologies
no
Is chronic PE suspected? VQ scan
McGoon et al. Chest 200412614S-34S
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Pulmonary Arterial Hypertension Detection and
Diagnosis
Is chronic PE suspected? VQ scan
yes
Is chronic PE confirmed and operable? Pulmonary
angiogram
yes
no
VQ normal
Anatomic definition (CT, MRI may provide
additional useful but not definitive
information) Thromboendarterectomy if
appropriate or medical treatment clotting
evaluation a/c
Is PAH due to lung disease or hypoxemia? PFTs,
arterial saturation
no
Dx parenchymal lung disease, hypoxemia, or sleep
disorder Medical treatment, oxygen, positive
pressure breathing as appropriate, and further
evaluation for other contributing causes,
including RHC if necessary
yes
no
Document exercise capacity regardless of cause of
PH Establish baseline, prognosis and document
progression/ response to treatment with serial
reassessments
What limitations are caused by the
PAH? Functional class 6-minute walk test
Document PA and RA pressures, PCWP (LV or LA
pressure if PCWP unobtainable or uncertain),
transpulmonary gradient CO, PVR, SvO2, response
to vasodilators Confirm PAH, or IPAH if no
other cause identified Discuss genetic testing
and counseling of IPAH
What are the precise pulmonary hemodynamics? RHC
McGoon et al. Chest 200412614S-34S
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NYHA Classification
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Right Heart Catheterization is the Diagnostic
Gold Standard

• Saturations
• Rule Out Shunts
• Intra-cardiac
• Intra-Pulmonary
• Hemodynamics
• RAP
• mPAP
• PCWP
• Rule out left sided heart disease
• CO/CI
• PVR
• Angiography
• Vessel properties
• CTEPH
• Vasodilator Response

RHC can also Prognosticate!
Rich et al. WHO Symposium on PPH. Evian,
France,1998.
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Therapeutic Pathways
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Therapies

• The only groups that have been approved for the
  specialized medications for pulmonary
  hypertension are Group 1 (pulmonary arterial
  hypertension/PAH) and Group 4 (CTEPH)
• The other groups require treatment of the
  underlying condition causing the elevated
  pressures.

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Therapeutic Options for PAH

• Traditional therapies

• FDA approved for PAH

• Supplemental O2
• Diuretics
• Oral vasodilators
• (CCB)
• Anticoagulants
• warfarin
• Inotropic agents
• Digitalis

• Prostanoids
• Epoprostenol (flolan/veletri)
• Treprostinil (IV/SQ/Inhaled)
• Inhaled Iloprost
• Oral treprostinil (Orenitram)
• ERAs
• Bosentan
• Ambrisentan
• Macitentan
• PDE-5 Inhibitors
• Sildenafil
• Tadalafil
• Guanylate Cyclase Stimulator
• Riociguat

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PAH Treatments ? a Historical Overview
IV treprostinil
CCB, anticoagulation, digitalis, diuretics
Riociguat Macitentan Orenitram
sildenafil
SC treprostinil
ambrisentan
epoprostenol
veletri
Iloprost
bosentan
2006
2010 2011 2012 2013
lt1995
1995
1996
1997
1998
1999
2000
2001
2002
2004
2005
2007
2009
2003
2008
tadalafil Inhaled treprostinil
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Prostanoids

• Prostacyclin (PGI2)- member of the eicosanoids
  family, inhibits platelet activation and
  effective vasodilator.
• Prostacyclin released by healthy endothelial
  cells.
• Deficiency in PAH patients
• Several routes of administration
• IV/parenteral, SQ, Inhaled, oral

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IV Prostanoids

• Epoprostenol- Flolan and Veletri
• Half-life approximately 2-5min
• Treprostinil- Remodulin
• Half-life several hours
• Both administered in ng/kg/min
• Dosing never changes even if weight does, start
  weight remains the same throughout duration of
  therapy.

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Single Lumen Hickman Catheter

• Never stop infusion
• Never draw labs from line
• Never flush

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CADD Legacy Pump
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SQ Prostanoids

• Treprostinil (Remodulin) SQ
• Small catheter placed in SQ tissue of the abdomen
• Site changed every 3-5 weeks

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Inhaled Prostanoids

• Iloprost (Ventavis)
• 6-9 treatments per day
• Fewer systemic effects than IV
• Treprostinil (Tyvaso)
• QID and dosed as breaths
• e.g. 3 breaths each inhalation that is increased
  by increments of 3 up to 9.
• Single person nebulizer
• Pt must bring in machine from home if hospitalized

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Inhaled Prostanoids

• Tyvaso

• Ventavis

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Oral Prostacyclin

• Treprostinil (Orinetram)
• Antiplatelet and vasodilatory actions, including
  pulmonary vasodilation
• FREEDOM-M trial (only study of 3 that met
  endpoint)
• Available as 0.125mg, 0.25mg, 1mg, 2.5mg ER BID
• Starting dose 0.25mg bid and titrated Q3d as
  tolerated
• Only showed improved 6MWD as monotherapy

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Endothelin Receptor Antagonist

• Endothelian-1 (ET-1) levels are increased in PAH
  and found in the precapillary pulmonary
  microvasculature which is the site of the
  increased vascular resistance in PAH.
• Two G protein-coupled receptors for ET-1 have
  been described ETA and ETB
• Bosentan- dual antagonist
• 62.5 to 125mg BID
• Ambrisentan- Selective ETA receptor
• 5-10mg daily
• Macitentan- Dual but with increased selectivity
  for ETA
• 10mg daily

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Phosphodiestrase-5 Inhibitors

• PDE5 Inhibitor- blocks the degradative action of
  phosphodiesterdase type 5 on cyclic GMP in smooth
  muscle cells resulting in vasodilation of the
  vessels.
• Sildenafil- 20-80mg TID
• Tadalafil- 20-40mg daily

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Guanylate Cyclase Stimulator

• Riociguat has a dual mode of action
• Synergist with endogenous nitric oxide
• Directly stimulating guanylate cyclase
  independent of NO availability
• Phase 3 trial in the NEJM 12 wk double-blind
  randomized placebo-controlled trial at 124
  centers in 30 countries for PAH patients showed
  improved walk distance and improvement in
  secondary end-points.

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Cost per Year

• Ambrisentan (Letairis)- 76,047.60
• Bosentan (Tracleer)- 76,543.20
• Tadalafil (Adcirca)- 18,316.80
• Epoprostenol (Flolan)- 34,170
• Oral Treprostinil (Orinetram)- 500,000
• Triple therapy can be over 130, 000/yr just for
  specialty medications.

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Ongoing Management

• Standard of care is for PAH patients to be
  established with a PH center for ongoing care.
• Multidisciplinary approach to care
• Patients on advance therapies to be seen every 3
  months if not more frequently
• Ongoing escalation of care, more evidence coming
  out showing the importance of combination
  therapies.

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Questions?