Evaluation of Elevated Pulmonary Arterial · PDF fileEvaluation of Elevated Pulmonary Arterial...
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Evaluation of Elevated Pulmonary Arterial Pressure
James R. Klinger, MD, FCCPProfessor of Medicine
Brown UniversityDirector - Pulmonary Hypertension Center
Rhode Island HospitalProvidence, Rhode Island
Faculty DisclosureWho What Why
Actelion Bosentan PAH
Bayer Riociguat* PAH, CTEPH
Gilead Ambrisentan PAH
Ikaria iNO PAH
Lung LX Treprostinil PAH
Pfizer Sildenafil PAH
United Therapeutics Tadalafil, treprostinil
PAH
* Pending FDA Approval
What is Pulmonary Hypertension?
Hemodynamic Definition:
Resting mPAP pressure ≥ 25 mmHg
mPAP, mean pulmonary arterial pressure
Pulmonary HypertensionHemodynamic Definition
Normal PA Pressures:
Normal PAP: mPAP 14.0 + 3.3 mmHg (PAP 25/9)+ 2 STD : mPAP 20.6 mmHg (PAP 34/14)Top Normal: mPAP 24 mmHg (PAP 40/16)
Grey Zone: mPAP 21-24Pulmonary hypertension mPAP > 25 mmHg
mPAP, mean pulmonary arterial pressure;
What is Pulmonary ArterialHypertension?
WHO Definition (2008): mPAP > 25 mmHg at rest Pulmonary venous pressure ≤ 15 mmHg
(PCWP, LAP, LVEDP)
PVR > 3 Wood units (ACCF/AHA Expert Consensus) mPAP > 30 mmHg with exercise?
PCWP, pulmonary capillary wedge pressure; PVR, pulmonary vascular resistance; LAP left atrial pressure, LVEDP left ventricular diastolic pressure
Transpulmonary Gradient/CO =Pulmonary Vascular Resistance Woods Unit
(mPAP –mPVP) / CO(15 – 10 mmHg) / 5 lpm =1 WU (TPG = 5 mmHg)
X 80 = 80 dyne.cm.s5
(25 – 10 mmHg) / 5 lpm =3 WU (TPG = 15 mmHg)X 80 = 240 dyne.cm.s5
(35 – 20 mmHg) / 5 lpm =3 WU (TPG = 15 mmHg)X 80 = 240 dyne.cm.s5
PAH – The REAL Definition
a DISEASE characterized by:
A pulmonary arterial vasculopathyMarkedly increased PVR due to vascular narrowingProgressive worsening that leads to RV failure and death
Histopathology of IPAH
Intima – endothelial proliferation Media‐ smooth muscle
proliferation/hypertrophy Thrombosis in situ
Photomicrographs courtesy Charles Kuhn,III MD
History of PAH 1889 - Pulmonary Sclerosis 1945 - Pulmonary Artery Catheterization 1951 – “Primary Pulmonary Hypertension” (PPH)
(Dreysdale et al) 1960s - Rapseed Oil and fenfluramine outbreaks 1970s - NIH Registry 1973 - Ist WHO PH Meeting 2003 - Evian, France – (PPH PAH) 2009 - Dana Point (Group 1’) 2013 – Nice, France ?
• 1976 -Prostacyclins • 1987 -Nitric oxide• 1991- Endothelin• 2000 – BMPR-2 gene
The 4th World Symposium on Pulmonary HypertensionDana Point, CaliforniaHeld February 2008
J Am Coll Cardiol .2009; 54 (1 Suppl): S1-S117.
Clinical Classification of Pulmonary Hypertension(Dana Point, CA – January, 2008)
1. PAH• Idiopathic PAH• Heritable• Drug- and toxin-induced• Persistent PH of newborn• Associated with:
−CTD−HIV infection−Portal hypertension−CHD−Schistosomiasis−Chronic hemolytic anemia
1’. PVOD and/or PCH
2. PH Owing to Left Heart Disease• Systolic dysfunction• Diastolic dysfunction• Valvular disease
3. PH Owing to Lung Diseases and/or Hypoxia• COPD• ILD• Sleep-disordered breathing• Alveolar hypoventilation disorders• Chronic exposure to high altitude• Developmental abnormalities
4. Chronic Thromboembolic (CTEPH)
5. PH With Unclear Multifactorial Mechanisms• Hematologic disorders• Systemic disorders• Metabolic disorders• Others
Simonneau G, et al. J Am Coll Cardiol. 2009;54;S43-S54.
PAVC RA RV PVPC
LA LV Ao
Pulmonary venous hypertensionElevated PCWP, normal PVR
PAHPH with respiratory diseaseCTEPHNormal PCWP, elevated PVR
PH: The Importance of Hemodynamics
PA
SVC
RA RV PVPC
LA LV Ao
IVC
< 15 mmHg< 6 mmHg
Pulmonary Arterial Hypertension is an Uncommon Cause of PH:
Armadale Echocardiography Study
Gabbay E, et al. Am J Respir Crit Care Med. 2007;175:A713.
Left heart disease, 78.7%
PAH, 2.3%
Congenital heart disease,
1.9%
Lung disease/sleep
related hypventilation,
9.7%
CETPH, 0.6%
Unknown, 6.8%
N = 483 of 4579 patients with sPAP > 40 mm Hg on echocardiography. PSAP = Pulmonary artery systolic pressure
Elevated PA Pressure
Group 1 Group 2 Group 3 Group 4 Group 5(PAH) Left Heart) (Lung) (PE) (Unclear)
PDE5I diuretics O2/CO2 Anticoagulate ?ERA antihypertensivesPGI2
Lung transplant MVR/AVR Lung transplant PA endarterectomy
Approach to Elevated Pulmonary Artery Pressure
Echocardiogram
PFT’s
Polysomnography
VQ Scan
• Sleep Disorder
• Chronic PE
Functional Test(6MWT, CPET)
Overnight Oximetry
History
Exam
CXR
ECG
HIV
ANA
LFT’s
RH Cath
TEE
Exercise Echo
Pulmonary Angiography
Chest CT Angiogram
Coagulopathy Profile
Vasodilator Test
Exercise RH Cath
Volume Loading
ABG’s
• Index of Suspicion of PH
• RVE, RAE, RVSP, RV Function
• Left Heart Disease• VHD, CHD
• Ventilatory Function• Gas Exchange
Other CTD Serologies
• HIV Infection
• Scleroderma, SLE, RA
• Portopulmonary HTN
• Establish Baseline• Prognosis
• Confirmation of PH• Hemodynamic Profile• Vasodilator Response
Pivotal Tests Contingent Tests Contribute to Assessment of:
Left Heart CathMcLaughlin VV, et al. J Am Coll Cardiol. 2009;53:1573‐1619.
ACC
F/AHA Diagn
ostic Algorith
m
Treatments for PAH
1995 2001 2002 2004 2005 2007 2009 2013 2014 ?
EpoprostenolBosentan
Sildenafil
Ambrisentan
Iloprost
Treprostinil SQ
Treprostinil Inhaled
Tadalafil
Treprostinil IV
Prostacyclins, ERAs PDE5Is, sGC+
Macitentan
Selexipeg
Oral Treprostinil ?
Beraprost?
Riociguat
Velitri
Mechanisms of PAH Pathogenesis
Humbert M et al. N Engl J Med. 2004;351:1425‐1436.
cGMP
cAMP
Vasoconstriction and proliferation
Endothelinreceptor A
Exogenous Exogenous nitric oxidenitric oxide
EndothelinEndothelin--receptor receptor
antagonistantagonistss
Endothelinreceptor B
Phosphodiesterase Phosphodiesterase type 5 inhibitortype 5 inhibitor
Vasodilationand antiproliferation
Phosphodiesterase type 5
Vasodilationand antiproliferation
Prostacyclin Prostacyclin derivativesderivatives
Nitric Oxide
Endothelin-1
Pre-proendothelin
L-arginine
Prostaglandin I2
L-citrulline
Nitric OxidePathway
EndothelinPathway
ProstacyclinPathway
Endothelial cellsProendothelin
Endothelial cellsArachidonic acid
Smooth muscle cells
Prostacyclin (prostaglandin I2)
Smooth muscle cells
Amlodipine, diltiazem, nifedipine (B)
YES
ACUTE RESPONDER
WHO Class I-IVAmlodipine, diltiazem,
nifedipine (B)
Sustained response (WHO I-II)
Atrial septostomy (E/B) and/orlung transplant (E/A)
INADEQUATE CLINICAL RESPONSE
NO
PAH Evidence‐Based Treatment Algorithm
Acute vasoreactivity test (A for IPAH)(E/C for APAH)
Expert referral (E/A)
Supportive therapy and general measures Avoid excessive physical exertion (E/A)Birth control (E/A)Psychosocial support (E/C)Infection prevention (E/A)
Oral anticoagulants (E/B) – IPAH/HPAHDiuretics (E/A)Oxygen (E/A)Digoxin (E/C)Supervised rehabilitation (E/B)
Strength of Recommendation NYHA Class II NYHA Class III NYHA Class IV
AAmbrisentan, Bosentan, Sildenafil
Ambrisentan, Bosentan,Epoprostenol IV, Iloprostinh, Sildenafil
Epoprostenol IV
B Sitaxsentan, Tadalafil Sitaxsentan, Tadalafil, Treprostinil SC
Inhaled Iloprost
C Beraprost Treprostinil SC
E/BIloprost IV, Treprostinil IV Iloprost IV, Treprostinil IV
Initial combination therapy (see below)
E/CAmbrisentan, Bosentan, Sildenafil, Sitaxsentan, Tadalafil
Not approved Treprostinil inh Treprostinil inh
Sequential combination therapy
PDE-5 I ERA + (B)
+ (B)+ (B)Prostanoids
NON-RESPONDER
4th World Symposium on PH. Dana Point, CA. 2008.Barst, et al. J Am Coll Cardiol. 2009;54:S78‐84.
INADEQUATE CLINICAL RESPONSE
Low Risk Determinants of Risk High Risk
No Clinical evidence of RV failure Yes
Gradual Disease progression RapidI,II NYHA functional class III, IV
Longer (> 400 meters) 6-MWD Shorter (< 300 meters)
Peak VO2 > 10.4 mL/kg/min Cardiopulmonary exercise testing Peak VO2 < 10.4 mL/kg/min
< 100 and stable BNP > 200 and rising
Minimal RV dysfunction ECHO findings Pericardial effusion, RV dysfunction, RA enlargement
RAP < 10 mm Hg; Hemodynamics RAP > 20 mm Hg;
CI > 2.5 L/min/m2Cardiac Output CI < 2 L/min/m2
McLaughlin, et al. Circulation. 2006;114:1417‐31.McLaughlin, et al. J Am Coll Cardiol. 2009;53:1573‐1619.
PAH Determinants of Patient RiskACC / AHA Expert Consensus
Summary, …when presented with elevation in PA pressure
Investigate possible causes Left heart disease COPD/pulmonary fibrosis/OSA Thromboembolic disease Connective Tissue Disease/HIV/Portal
Hypertension Treat underlying conditions Assess severity of dyspnea (NYHA class I‐IV) Cardiac catheterization/Vasodilator Trial Select appropriate medical therapy
Consider referral to PH Center