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