Transcript Exercise Hemodynamics: A Look Into The RV

Pulmonary Hypertension:
New Insights into a
Complex Disease
Rajeev Saggar, MD
Academic Chair, Pulmonary Division
Assoc. Prof of Medicine, Univ of Arizona
Co-Director of Lung Transplant, Univ of Arizona
Banner Good Samaritan Hospital
Conflicts of Interest


I have no conflicts related to the content of this
topic
I will discuss the use of treprostinil “off-label”
Characteristics of Pulmonary Circulations

Low pressure system


Low resistance


~One seventh the resistance of
systemic circulation
High capacitance


One fifth the pressures of
systemic circulation, despite same
CO as systemic circulation
Accommodates 5- to 6-fold ↑ in
blood flow with only 2-fold ↑ in
PAP
Dynamic vascular bed

V:Q matching; vasodilatation and
recruitment
5th World Symposium on Pulmonary Hypertension
(WSPH) Consensus Definitions
Pulmonary Hypertension (PH)
Mean pulmonary artery pressure (mPAP)
≥25 mm Hg
Pulmonary Arterial Hypertension (PAH)
Mean pulmonary artery pressure (mPAP)
≥25 mm Hg
with
Mean pulmonary artery occlusion pressure (PAOP)
≤15 mm Hg
and
Pulmonary vascular resistance (PVR)
>3 Wood units
As measured by right-heart catheterization.
Hoeper MM, et al. J Am Coll Cardiol. 2013;62:D42-50.
Right Ventricular Structure
● The RV is triangular in
shape
● Divided into 3 regions
-
Inlet
Apex
Infundibulum or Conus
● Contraction proceeds from
inlet to infundibulum
● Capacitance of large
PAs accommodates
stroke volume, keeps
pressure low
Haddad F, et al. Circulation. 2008;117:1436-1448.
Pathophysiology of RV Dysfunction in
PAH
PAH
RV pressure overload
↑ RV wall stress
Neurohormonal and
immunological activation
Altered bioenergetics
(Ischemia, myocardial remodeling)
Genetic
determinants
Myocardial Remodeling
Hypertrophy; matrix remodeling
Increase in RV contractility
Ischemia
Adaptive Remodeling
Maladaptive Remodeling
Dilatation and failure
Vonk-Noordegraaf A, et al. J Am Coll Cardiol. 2013;62:D22-33.
6
Arrhythmias
Idiopathic PAH
Stacher et al: AJRCCM 186: 261-272
What do we measure as a fluid
pressure?
Zero Reference Level (ZRL)
Measuring bridge
P is set on zero.
i.e. the difference from atmospheric pressure is set to zero.
How does P change now?
A: P goes up
B: P goes down
C: P does not change
Zero Reference Level (ZRL)
Measuring bridge
i.e. P depends solely on ZRL and fluid top
ZRL Definition:

Zero Reference Level must be defined
anatomically

In relation to the heart

Top right atrium


Center right atrium


Eyster 1929
Center left atrium


Moritz&Tabora 1910
V. Recklinghausen 1906; Courtois 1990; Seo 2007
In relation to the supine body

5 cm below sternal skin surface


Moritz&Tabora 1910; Braunwald 1961
10 cm above table

Lyons 1938
Does ZRL really matter?
5 cm below sternal surface
1/3 thoracic diameter
1/2 thoracic diameter
10 cm above table
N=149 patients by thoracic diameter
Kovacs G, Olschewski H et al 2013, submitted
Pulmonary Fibrosis-PH
IVS
RV
LV
RA
LA
Vascular Pathology is Similar in the
Arteries, but NOT the VEINS
artery
Saggar et al: Manuscript in preparation
UCLA Quantitative Pathology Analysis of
Explanted Lung Tissue
The veins (not the arteries) distinguish the cohorts
Unpublished Data
Background:

Pulmonary Fibrosis (PF):
 Idiopathic interstitial pneumonias (IIP)

Idiopathic pulmonary fibrosis (IPF)
 Connective
Tissue Disease related PF
 Sarcoidosis
 Combined
(CPFE)
 Others
pulmonary fibrosis-emphysema
Baseline Factors Influencing
Survival: IPF
Poor Survival:
 moderate/severe [hurrying on
the flat or after one flight of
stairs/breathless at rest or on
minimal exertion]dyspnea (3.5yrs)
 DLco < 35%
 SaO2  88% during the 6MWT


mPA > 25mmHg



4-fold increase death
Better Survival:
 mild dyspnea [hurrying on
hills or after two flights of
stairs] (8-yrs)
 DLco > 35%
 SaO2 > 88% during the
6MWT
 mPA < 25mmHg
1-year mortality 28%
HRCT definite UIP and biopsy
UIP
 Survival 2.1 years
HRCT indeterminate and biopsy
UIP
 Survival 5.8 years


1-year mortality 5.5%
HRCT indeterminate and
biopsy NSIP
 Survival 9.1 years
Turner-Warwick M, et al.Thorax. 1980;35:171-180.
Latsi PI, et al. Am J Respir Crit Care Med. 2003;168:531-537.
Lama VN, et al. Am J Respir Crit Care Med. 2003;168:1084-1090.
Lettieri CJ, et al. Chest. 2006;129:746-752.
Flaherty KR, et al. Thorax. 2003;58:143-148.
Pulmonary Fibrosis and PH



Prevalence of IPF 14 to 42.7 cases per 100,000
population
PH can complicate the clinical course of IPF and should
prompt earlier evaluation for LT
Prevalence of PH reported 30%% in IPF patients

No FDA approved therapies exist for interstitial or
vascular component of IPF:
 Bosentan
 Ambrisentan
 Sildenafil
 Macitentan

Lung transplantation (LT) final option
27
Overview:
Pulmonary Hypertension: Rational Target?

Echo estimates of sPAP have strong correlation with survival in IPF
 sPAP>50mmHg: median survival 0.7 years (Nadrous 2005)
 sPAP<50mmHg: median survival > 4 years

Limited RHC data in IPF:
 mPA > 25 mmHg
 (+) PH: 1 year mortality 28% (Lettieri 2006)
 (-) PH: 1 year mortality 5.5%

Pulmonary Vascular Resistance (PVR): Pulmonary Fibrosis
 PVR > 6.23 WU: 8-fold increase mortality 1-year (Corte
2009)
 PVR> 6 WU: 1-year survival 47% in CPFE (Cottin 2010)
Pulmonary Fibrosis
How PH may affect the peri-lung transplant setting

IPF patients awaiting Lung Transplantation


38% have PH at baseline
At time of transplant: 86% have PH

Rate of change of mPA: 3.8 mmHg/month

Pre-transplant PH associated with IPF is a strong,
continuous risk factor for allograft dysfunction post-lung
transplantation

Primary graft dysfunction (PGD) associated with each
10-mmHg increase pre-transplant mPAP was OR 1.64
Fang et al: Chest. 2011 Apr;139(4):782-7
Shorr et al: Eur Respir J. 2007 Oct;30(4):715-21
So What Options Remain?

No FDA approved therapies exist for interstitial or
vascular component of IPF:
 Bosentan
 Ambrisentan
 Sildenafil
 Macitentan

What about prostanoid therapy?

Treprostinil or epoprostenol
33
Potential Concerns:

Anecdotal experience raises concerns of using
parenteral prostanoid in PF-PH (and other ILD-PH)

Concerns of unmasking venous disease, leading to pulmonary
edema

Acute worsening V/Q mismatch and increase oxygen
requirements (Ghofrani 2002: Lancet)
 ?Acute
changes translate to long term outcome?
34
Acute Administration MIGET Studies in
PF & Group I PAH
Increased intrapulmonary shunt does not necessarily translate to worsened
paO2
PF Type or
Group I PAH
n
PH
Drug
Aggressive
uptitration
Exercise
Ghofrani
(2002)
Heterogeneous
16
Y (mPAP 41 median)
iNO/epo/sild
Y
N
Blanco
(2010)
IPF
7
N (mPAP 20 on RA)
iNO
-
Y
Gunther
(2007)
IPF
12
N (mPAP 22.4)
bosentan
-
N
Agusti
(1991)
IPF
15
N (mPAP 20)
O2
-
Y
Walmrath
(1995)
Heterogeneous
6
Y (mPAP 38)
inhPGI2
-
N
Olschewski
(1999)
Heterogeneous
8
Y (mPAP 40.2)
IV iloprost
Y
N
Group I PAH
CTEPH
15
Y (range mPAP 42 to 80)
O2/nitropr/isop
Y
N
Group I PAH
7
Y (mPAP 49)
epo/inh ilop
Y
N
Dantzker
(1981)
Bratel
(2007)
V/Q inequality
increased shunt (4.8% to 16.8%) and
hypoxemia with epo;
unchanged PVR/SVR
iNO does not affect V/Q inequality while
improving pulmonary hemodynamics (but no
effect on CO)
decrease in %shunt;
no change in gas exchange
↑log SD Q to 100% oxygen at rest↓V/Q
inequality at rest & exercise↓exercise
PAP↓exercise hypoxemia
worsened paO2 and P/F ratio and
nonsignificant increases in shunt and low
V/Q perfusion
worsened shunt (5.1% to 23.1%);
nonsignificant decrease in SaO2; PVR/SVR
unchanged
worsened V/Q inequality (increase shunt,
increase perfusion to low V/Q, or both)
epo ↑shunt, PVR/SVR, HR, svO2;
no change in paO2 or SaO2
Purpose:

The purpose of this investigation was to assess the effects of
chronic parenteral treprostinil administration on functional,
hemodynamic, and right heart function parameters in patients
referred to LT in a PF population with an advanced PH
phenotype, characterized by a markedly increased PVR and
significant RV dysfunction.

Due to a lack of supportive data in this context, we studied this
population on a compassionate basis, either as a bridge to LT or
to achieve clinical stabilization in transplant ineligible patients,
whom we believe were at risk of clinical deterioration due to
significant pulmonary hypertension and right heart dysfunction
Index Case:
IVS
RV
LV
RA
LA
Index Case:
Saggar et al: JHLT 2010: 1210-7
Changes in Hemodynamics & Echocardiographic Function in an
Advanced Phenotype of PH and Right Heart Dysfunction
associated with Pulmonary Fibrosis (PF)
N=15 hypoxic, pre lung transplant PF patients treated with parenteral treprostinil
Inclusion: mPA > 35mmHg and PVR > 4 WU
Echocardiogram: + RV dysfunction
Saggar et al: Thorax 2014; 69
Saggar et al: Thorax 2014; 69
Importance of the Advanced PF-PH
Clinical Phenotype
RV Function
Saggar et al: Thorax 2014; 69
RV dysfunction may be necessary
for PH-targeted therapy success

Sildenafil IPF-NET study: evaluation of 119
echocardiograms prior to sildenafil vs. placebo

Patients with RV systolic dysfunction and sildenafil had
preservation of exercise capacity and improved QOL,
compared to placebo
Han MK et al Chest 2013;143(6)
Saggar R et al Thorax 2014
Improved Transplant-Free Survival in Patients with Systemic
Sclerosis-Associated Pulmonary Hypertension and Interstitial
Lung Disease
SScPH
1-yr: 82%
2-yr: 58%
3-yr: 47%
SSc-ILD-PH
1-yr: 78%
2-yr: 46%
3-yr: 28%
Volkmann, Saggar et al: Arthritis & Rheum 2014; 1900-8
Improved Transplant-Free Survival in Patients with Systemic
Sclerosis-Associated Pulmonary Hypertension and Interstitial
Lung Disease
Volkmann, Saggar et al: Arthritis & Rheum 2014; 1900-8
1. No difference in survival between SSc-PH and SSc-PF-PH
2. Early prostanoid initiation (<6 months after diagnostic
RHC) is an independent predictor of survival
SSc-PAH
SSc-PH-ILD
Volkmann, Saggar et al: Arthritis & Rheum 2014; 1900-8
Conclusions

The appropriate clinical PF-PH phenotype most likely to
respond to PH-targeted therapy would be circulatory-limited and
may include:




Advanced pulmonary hemodynamics (mPAP>35; PVR>4 WU)
Echocardiographic RV dysfunction at baseline ( TAPSE, eccentricity
index and RV end diastolic area)
Our group has clinically demonstrated safe and efficacious use of
infusional prostanoid therapy for PF-PH in the pre-lung
transplant setting (heterogeneous PF) and with SSc-PF-PH
Future clinical trials should consider this specific PF-PH
phenotype (Phase 3 funded)
Special Thanks
UCLA Pulmonary & Critical Care
Rajan Saggar, MD
John Belperio MD
David Ross MD
Joseph Lynch III MD
PH Nursing
Lynne Yoder RN
Kathy McCloy ANP
Glenna Traiger CSN
Amber Porter, FNP
Deanna Kalina, RN
UCLA Rheumatology
Dan Furst MD
Philip Clements MD
Elizabeth Volkmann MD
Suzanne Kafaja MD
University of Michigan Rheumatology
Dinesh Khanna MD
Temple University Cardiology
Paul Forfia MD
UCLA Cardiothoracic Surgery
Abbas Ardehali MD
Curtis Hunter MD
Murray Kwon MD
Reshma Binwale MD
UCLA Pathology
Michael Fishbein MD
Greg Fishbein MD
Dean Wallace MD
Atsuko Seki MD