Assessing the Right Ventricle in
Pulmonary Arterial Hypertension:
Getting 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
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
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
Hemodynamic Definition of PH/PAH
PH
Mean PAP ≥ 25 mm Hg
PAH
Mean PAP ≥ 25 mm Hg plus
PCWP/LVEDP ≤ 15 mm Hg
ACCF/AHA CECD includes PVR > 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. 2009;53:1573-1619.
Badesch D, et al. J Am Coll Cardiol. 2009;54:S55-S66.
Clinical Classification of PH
1. 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 Venoocclusive Disease and
Pulmonary Capillary
Hemangiomatosis
2. PH Due to Left Heart
Disease
• Systolic dysfunction
• Diastolic dysfunction
• Valvular disease
Simonneau G, et al. J Am Coll Cardiol. 2009;54:S43-S54.
Clinical Classification of PH (cont)
3. PH Due to Lung Diseases and/or
Hypoxia
4. Chronic Thromboembolic
PH
• Chronic obstructive pulmonary
disease
5. PH With Unclear or
Multifactorial
• Interstitial lung disease
Mechanisms
• Other pulmonary diseases with
mixed restrictive and obstructive
• Hematologic disorders
pattern
• Systemic disorders
• Sleep-disordered breathing
• Metabolic disorders
• Alveolar hypoventilation disorders • Others
• Chronic exposure to high altitude
• Developmental abnormalities
Simonneau G, et al. J Am Coll Cardiol. 2009;54:S43-S54.
Pathogenesis of PAH
1 Risk Factors and
2 Vascular Injury
Endothelial Dysfunction
Associated Conditions
Collagen Vascular Disease
Congenital Heart Disease
Portal Hypertension
HIV Infection
Susceptibility
Drugs and Toxins Abnormal BMPR2 Gene
Other Genetic Factors
Pregnancy
Adventitia
Media
Intima
↓ Nitric Oxide Synthase
↓ Prostacyclin Production
↑ Thromboxane Production
↑ Endothelin 1 Production
Vascular Smooth Muscle Dysfunction
Impaired Voltage-Gated
Potassium Channel (KV1.5)
Smooth muscle
hypertrophy
Early intimal
proliferation
Normal
3 Disease Progression
Loss of Response to
Short-Acting
Vasodilator Trial
Smooth muscle
hypertrophy
Adventitial and
intimal proliferation
In situ
thrombosis
Plexiform
lesion
Reversible Disease
Gaine S. JAMA. 2000;284:3160-3168.
Irreversible Disease
French Registry: Kaplan-Meier Survival
Estimates in Combined PAH Population vs
NIH-Predicted
100
Observed
80
Survival
(%)
60
Predicted (NIH Registry)
40
20
0
0
No. at risk:
All patients
12
24
36
Time (months)
56
69
98
113
120
Humbert M, et al. Circulation. 2010;122:156-163.
127
133
Survival of Patients With Idiopathic PAH
According to NYHA FC at Diagnosis
100
80
NYHA FC I/II
60
NYHA FC III
40
NYHA FC IV
20
N = 190
0
0
12
24
36
Time (months)
FC = functional class
Humbert M, et al. Circulation. 2010;122:156-163.
McLaughlin VV, et al. J Am Coll Cardiol. 2009;53:1573-1619.
Mild PAH
Systole in short-axis view
Apical 4-chamber view
RV
IVS
LV
Diastole in short-axis view
TR Jet
Moderate PAH Disease
Systole
Diastole
Apical 4-Chamber View
TR Jet
Severe PAH and RV Failure
Systole
Apical 4-Chamber View
Diastole
TR Jet
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 < 1.8 cm has negative prognostic implications
Forfia PR, et al. Am J Respir Crit Care Med. 2006;174:1034-1041.
Progression of PAH
Presymptomatic/
Compensated
CO
Symptomatic/
Decompensating
Declining/
Decompensated
Symptom
Threshold
PAP
PVR
Time
Right Heart
Dysfunction
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. 2007;
9(suppl H):H29-34.
Cardiac MRI in PH
Anterior
Chest Wall
Left Lung
IVS
LV
RV
Liver
Normal short-axis cine
MRI
Short-axis cine in severe PH
PAH Treatment Goals
• Fewer/less severe symptoms
• Improved exercise capacity
• Improved hemodynamics
• Prevention of clinical worsening
• Improved quality of life
• Improved survival
PAH Determinants of Risk
Lower Risk
Determinant of Risk
Higher Risk
No
Clinical evidence of
RV failure
Yes
Progression of
symptoms
Rapid
WHO class
IV
6-minute walk
distance
Shorter (< 300 m)
Gradual
II, III
Longer (> 400 m)
McLaughlin V, et al. J Am Coll Cardiol. 2009;53:1573-1619.
PAH Determinants of Risk (cont)
Lower Risk
Peak VO2 > 10.4
mL/kg/min
Minimal RV
dysfunction
RAP < 10 mm Hg;
CI > 2.5 L/min/m2
Minimally elevated
Determinant of Risk
Higher Risk
CPET
Peak VO2 < 10.4
mL/kg/min
Echocardiography
Pericardial effusion,
significant RV
enlargement/dysfunction; RA enlargement
Hemodynamics
RAP > 20 mm Hg;
CI < 2.0 L/min/m2
BNP
Significantly elevated
McLaughlin V, et al. J Am Coll Cardiol. 2009;53:1573-1619.
What Is the Optimal Treatment Strategy?
Anticoagulate ± Diuretics ±
Oxygen ± Digoxin
Acute Vasoreactivity Testing
Positive
Negative
Oral CCB
Lower Risk
No
Sustained
Response
Yes
Continue CCB
No
Gradual
II, III
Longer (> 400 m)
Peak VO2 > 10.4
mL/kg/min
Minimal RV
dysfunction
RAP < 10 mm Hg;
CI > 2.5 L/min/m2
Minimally elevated
Determinants of Risk
Higher Risk
Clinical evidence of
RV failure
Progression of
symptoms
WHO class
6MWD
IV
Shorter (< 300 m)
CPET
Peak VO2 < 10.4 mL/kg/min
Echocardiography
Hemodynamics
BNP
Yes
Rapid
Pericardial effusion,
significant RV enlargement/
dysfunction; RA enlargement
RAP > 20 mm Hg;
CI < 2.0 L/min/m2
Significantly elevated
McLaughlin V, et al. J Am Coll Cardiol. 2009;53:1573-1619.
ACCF/AHA Consensus PAH Treatment
Algorithm
Anticoagulants ± Diuretics ±
Oxygen ± Digoxin
Positive
Acute Vasoreactivity
Testing
Negative
Oral CCB
Lower risk
Higher risk
Sustained
Response
ERAs or PDE5 inhibitors
(oral), epoprostenol or
treprostinil (IV), iloprost
(inhaled), treprostinil (SC)
Epoprostenol or
treprostinil (IV),
iloprost (inhaled),
ERAs or PDE5
inhibitors (oral),
treprostinil (SC)
No
Yes
Continue
CCB
Reassess – consider
combination therapy
Investigational protocols
Atrial septostomy
Lung transplant
McLaughlin VV, et al. J Am Coll Cardiol. 2009;53:1573-1619.
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
WHO functional class
IV
6MW distance
< 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
Treatment
IV prostacyclin and/or combination
treatment
I/II
> 400 m
Oral therapy
McLaughlin V et al. J Am Coll Cardiol. 2009;53:1573-1619.
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
Echocardiography
Every 6-12 months or center
dependent
BNP
Center dependent
Right heart
catheterization
Every 6-12 months or clinical
deterioration
Every 12 months or center
dependent
Center dependent
Clinical deterioration and
center dependent
McLaughlin V, et al. J Am Coll Cardiol. 2009;53:1573-1619.
Prostacyclin Use in REVEAL® (N = 2438)
Badesch DB, et al. Chest. 2010;137:376-387.
Important Prognostic Variables
• French Registry
–
–
–
–
–
–
–
Functional class
6-minute walk
RAP
Cardiac index
Age
Gender
Etiology
DLCO = carbon-monoxide diffusing capacity
• REVEAL Registry
–
–
–
–
–
–
–
–
–
–
Functional class
6-minute walk
PVR, RAP
Vitals
BNP
Pericardial effusion
DLCO
Age
Gender
Etiology
Humbert M, et al. Circulation. 2010;122:156-163.
Benza RL, et al. Circulation. 2010;122:164-172.
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. 2010;122:156-163.
Benza RL, et al. Circulation. 2010;122:164-172.
Effective PAH Management: Early
Intervention, Regular Monitoring, and
Escalation of Treatment
Functional Capacity
No functional impairment
Late intervention
Time
Progressive remodeling
and right heart failure
in absence of treatment
Effective PAH Management: Early
Intervention, Regular Monitoring, and
Escalation of Treatment (cont)
Functional Capacity
No functional impairment
Will escalation of therapy and achievement of goals
improve long-term outcomes?
Early intervention
Late intervention
Time
Progressive remodeling
and right heart failure
in absence of treatment
Candidate "Goals of Therapy"
• Functional class I/II
• 6-minute walk distance
• Hemodynamics
– RAP
– Cardiac output/cardiac index
• BNP
• ? Echocardiography
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