Assessing the Right Ventricle in Pulmonary Arterial Hypertension: Getting to the Heart of the Matter

1
Assessing the Right Ventricle in Pulmonary
Arterial HypertensionGetting to the Heart of
the Matter

• Vallerie V. McLaughlin, MD
• Professor of Medicine
• Director, Pulmonary Hypertension Program
• Department of Internal Medicine
• Division of Cardiovascular Medicine
• University of Michigan Health System
• Ann Arbor, Michigan

2
Goals

• Summarize the role of diagnostic testing to
  evaluate the right ventricle in patients with PAH
• Explore emerging as well as existing diagnostic
  tools
• Evaluate the relevance of the diagnostic findings
  in risk stratification and the utilization of
  appropriate therapies

3
Disclosures
Vallerie V. McLaughlin, MD has disclosed the
following relevant financial relationships
Served as a consultant and/or on a speakers
bureau and/or has received grants/research
support from Actelion Pharmaceuticals, Ltd
Bayer Healthcare Pharmaceuticals Gilead
Sciences, Inc. Novartis Pharmaceuticals
Corporation United Therapeutics Corporation
4
Hemodynamic Definition of PH/PAH

PH
Mean PAP 25 mm Hg
Mean PAP 25 mm Hg plusPCWP/LVEDP 15 mm Hg
PAH
ACCF/AHA CECD includes PVR gt 3 Wood units
PH pulmonary hypertension PAH pulmonary
arterial hypertension PAP pulmonary arterial
pressure PCWP pulmonary capillary wedge
pressure LVEDP left ventricular end-diastolic
pressure ACCF American College of Cardiology
Foundation AHA American Heart Association
CECD Clinical Expert Consensus Document PVR
pulmonary vascular resistance
McLaughlin VV, et al. J Am Coll Cardiol.
2009531573-1619. Badesch D, et al. J Am Coll
Cardiol. 200954S55-S66.
5
Clinical Classification of PH

• PAH
• Idiopathic PAH
• Heritable
• Drug- and toxin-induced
• Persistent PH of newborn
• Associated with
• Connective tissue disease
• HIV infection
• Portal hypertension
• Congenital heart disease
• Schistosomiasis
• Chronic hemolytic anemia

• 1. Pulmonary Veno-occlusive Disease and
  Pulmonary Capillary Hemangiomatosis
• PH Due to Left Heart Disease
• Systolic dysfunction
• Diastolic dysfunction
• Valvular disease

Simonneau G, et al. J Am Coll Cardiol.
200954S43-S54.
6
Clinical Classification of PH (cont)

• 3. PH Due to Lung Diseases and/or Hypoxia
• Chronic obstructive pulmonary disease
• Interstitial lung disease
• Other pulmonary diseases with mixed restrictive
  and obstructive pattern
• Sleep-disordered breathing
• Alveolar hypoventilation disorders
• Chronic exposure to high altitude
• Developmental abnormalities

• 4. Chronic Thromboembolic PH
• 5. PH With Unclear or Multifactorial Mechanisms
• Hematologic disorders
• Systemic disorders
• Metabolic disorders
• Others

Simonneau G, et al. J Am Coll Cardiol.
200954S43-S54.
7
Pathogenesis of PAH
Risk Factors andAssociated Conditions Collagen
Vascular Disease Congenital Heart Disease Portal
Hypertension HIV Infection Drugs and
Toxins Pregnancy
Vascular Injury Endothelial Dysfunction ? Nitric
Oxide Synthase ? Prostacyclin Production ?
Thromboxane Production ? Endothelin 1
Production Vascular Smooth Muscle
Dysfunction Impaired Voltage-Gated Potassium
Channel (KV1.5)
Disease Progression Loss of Response to
Short-Acting Vasodilator Trial
1
2
3
Susceptibility Abnormal BMPR2 Gene Other Genetic
Factors
Smooth muscle hypertrophy
Adventitial and intimal proliferation
In situ thrombosis
Adventitia
Smooth muscle hypertrophy
Media
Intima
Plexiform lesion
Early intimal proliferation
Gaine S. JAMA. 20002843160-3168.
8
French Registry Kaplan-Meier Survival Estimates
in Combined PAH Population vs NIH-Predicted
Observed
Survival ()
Predicted (NIH Registry)
Time (months)
Humbert M, et al. Circulation. 2010122156-163.
9
Survival of Patients With Idiopathic PAH
According to NYHA FC at Diagnosis
100
NYHA FC I/II
80
NYHA FC III
60
40
NYHA FC IV
20
N 190
0
36
12
24
0
Time (months)
FC functional class Humbert M, et al.
Circulation. 2010122156-163.
10
McLaughlin VV, et al. J Am Coll Cardiol.
2009531573-1619.
11
Mild PAH
Apical 4-chamber view
Systole in short-axis view
RV
IVS
LV
Diastole in short-axis view
TR Jet
12
Moderate PAH Disease
Systole
Apical 4-Chamber View
TR Jet
Diastole
13
Severe PAH and RV Failure
Apical 4-Chamber View
Systole
TR Jet
Diastole
14
Tricuspid Annular Plane Systolic Excursion (TAPSE)

• Contraction of the RV is mainly longitudinal, and
  the tricuspid annulus displaces toward apex
  during systole
• Imaging through lateral RV free wall with M-mode
  assesses longitudinal displacement (excursion) of
  the tricuspid annulus
• Less TAPSE occurs when RV function declines
• Baseline TAPSE lt 1.8 cm has negative prognostic
  implications

Forfia PR, et al. Am J Respir Crit Care Med.
20061741034-1041.
15
Progression of PAH
CO
Symptom Threshold
PAP
Right Heart Dysfunction
PVR
Time
16
Role of MRI in PAH Assessment

• Quantify RV size, function, viability, and
  interaction with LV
• Evaluate pulmonary vascular structure and
  function
• Combining volumetric and flow to pressure
  measurements can improve RV function and
  afterload assessment
• Application in PAH is still in growing phase

.
Vonk-Noordegraaf A, et al. Eur Heart J.
20079(suppl H)H29-34.
17
Cardiac MRI in PH
Anterior Chest Wall
Left Lung
LV
IVS
RV
Liver
Normal short-axis cine MRI
Short-axis cine in severe PH
18
PAH Treatment Goals

• Fewer/less severe symptoms
• Improved exercise capacity
• Improved hemodynamics
• Prevention of clinical worsening
• Improved quality of life
• Improved survival

19
PAH Determinants of Risk
Lower Risk Determinant of Risk Higher Risk
No Clinical evidence ofRV failure Yes
Gradual Progression of symptoms Rapid
II, III WHO class IV
Longer (gt 400 m) 6-minute walk distance Shorter (lt 300 m)
McLaughlin V, et al. J Am Coll Cardiol.
2009531573-1619.
20
PAH Determinants of Risk (cont)
Lower Risk Determinant of Risk Higher Risk
Peak VO2 gt 10.4 mL/kg/min CPET Peak VO2 lt 10.4 mL/kg/min
Minimal RV dysfunction Echocardiography Pericardial effusion,significant RV enlargement/dysfunc-tion RA enlargement
RAP lt 10 mm HgCI gt 2.5 L/min/m2 Hemodynamics RAP gt 20 mm HgCI lt 2.0 L/min/m2
Minimally elevated BNP Significantly elevated
McLaughlin V, et al. J Am Coll Cardiol.
2009531573-1619.
21
What Is the Optimal Treatment Strategy?
Anticoagulate Diuretics Oxygen Digoxin
Lower Risk Determinants of Risk Higher Risk
No Clinical evidence ofRV failure Yes
Gradual Progression of symptoms Rapid
II, III WHO class IV
Longer (gt 400 m) 6MWD Shorter (lt 300 m)
Peak VO2 gt 10.4 mL/kg/min CPET Peak VO2 lt 10.4 mL/kg/min
Minimal RV dysfunction Echocardiography Pericardial effusion,significant RV enlargement/dysfunction RA enlargement
RAP lt 10 mm HgCI gt 2.5 L/min/m2 Hemodynamics RAP gt 20 mm HgCI lt 2.0 L/min/m2
Minimally elevated BNP Significantly elevated
McLaughlin V, et al. J Am Coll Cardiol.
2009531573-1619.
22
ACCF/AHA Consensus PAH Treatment Algorithm
Anticoagulants Diuretics Oxygen Digoxin
Acute Vasoreactivity Testing
Positive
Negative
Oral CCB
Lower risk
Higher risk
Sustained Response
Yes
Continue CCB
McLaughlin VV, et al. J Am Coll Cardiol.
2009531573-1619.
23
Longitudinal Evaluation of the Patient
Stable no increase in symptoms and/or decompensation Clinical course Unstable increase in symptoms and/or decompensation
No evidence of right heart failure Physical exam Signs of right heart failure
I/II WHO functional class IV
gt 400 m 6MW distance lt 300 m
RV size/function normal Echocardiography RV enlargement/dysfunction
RAP normal CI normal Hemodynamics RAP high CI low
Near normal, remaining stable, or decreasing BNP Elevated or increasing
Oral therapy Treatment IV prostacyclin and/or combination treatment
McLaughlin V et al. J Am Coll Cardiol.
2009531573-1619.
24
Longitudinal Evaluation (cont)
Stable no increase in symptoms and/or decompensation Clinical course Unstable increase in symptoms and/or decompensation
Every 3-6 months Frequency of evaluation Every 1-3 months
Every clinic visit Functional class assessment Every clinic visit
Every clinic visit 6MW distance Every clinic visit
Every 12 months or center dependent Echocardiography Every 6-12 months or center dependent
Center dependent BNP Center dependent
Clinical deterioration and center dependent Right heart catheterization Every 6-12 months or clinical deterioration
McLaughlin V, et al. J Am Coll Cardiol.
2009531573-1619.
25
Prostacyclin Use in REVEAL (N 2438)
Badesch DB, et al. Chest. 2010137376-387.
26
Important Prognostic Variables

• French Registry
• Functional class
• 6-minute walk
• RAP
• Cardiac index
• Age
• Gender
• Etiology

• REVEAL Registry
• Functional class
• 6-minute walk
• PVR, RAP
• Vitals
• BNP
• Pericardial effusion
• DLCO
• Age
• Gender
• Etiology

DLCO carbon-monoxide diffusing capacity
Humbert M, et al. Circulation. 2010122156-163. B
enza RL, et al. Circulation. 2010122164-172.
27
Will a Change in Important Prognostic Variables
Change Outcomes?

• French Registry
• Functional class
• 6-minute walk
• RAP
• Cardiac index
• Age
• Gender
• Etiology

• REVEAL Registry
• Functional class
• 6-minute walk
• PVR, RAP
• Vitals
• BNP
• Pericardial effusion
• DLCO
• Age
• Gender
• Etiology

Humbert M, et al. Circulation. 2010122156-163. B
enza RL, et al. Circulation. 2010122164-172.
28
Effective PAH Management Early Intervention,
Regular Monitoring, and Escalation of Treatment
No functional impairment
Functional Capacity
Progressive remodeling and right heart
failure in absence of treatment
Late intervention
Time
29
Effective PAH Management Early Intervention,
Regular Monitoring, and Escalation of Treatment
(cont)
No functional impairment
Will escalation of therapy and achievement of
goals improve long-term outcomes?
Functional Capacity
Early intervention
Progressive remodeling and right heart failure in
absence of treatment
Late intervention
Time
30
Candidate "Goals of Therapy"

• Functional class I/II
• 6-minute walk distance
• Hemodynamics
• RAP
• Cardiac output/cardiac index
• BNP
• ? Echocardiography

31

• Thank you for participating in this CME activity.
• To proceed to the online CME test, click on the
  Earn CME link on this page.