Download Pulmonary hypertension in LV dysfunction

Pulmonary hypertension in LV
dysfunction
Dr Angela Worthington
April 5th 2011
Overview
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Normal pulmonary physiology
Pathophysiology
Clinical research
Therapeutic trials
The Right Ventricle
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RV is thin walled and
distensible
Significant component of
ejection function comes from
bellows effect conferred by
negative and positive intrathoracic pressure.
Normal RV can generate
systolic pressures up to 4550mmHg
Hypertrophied RV can
generate higher pressures
Pulmonary
circulation
•Low
pressure, high capacity
system.
•Same
volume as systemic
circulation
•Normal
pulmonary
pressure <25mmHg
•Normal
PVR is 67+/-30
dynes
•
Less than 10% of
SVR
•Main
determinant of RV
afterload and output
•Even
small rises if PAP can
result in RV dysfunction
Figure 1.
A: transverse section of a pulmonary capillary
endothelial cell. At the level of the alveolar capillary
unit, processing of vasoactive substances is likely to
be maximal. Cells are extremely thin but present a
vast surface area that is further enhanced by
caveolae and surface projections.
B: immunocytochemical localization of angiotensinconverting enzyme on plasma membrane of a
pulmonary endothelial cell in culture including
caveolae (arrow) and projection (*). The endothelial
surface is not only extensive but contains specific
enzymes accessible to circulating substrates.
C: vasoactive peptides are not only inactivated
during circulation through the lungs but also exert
effects on pulmonary vascular tone. The mechanism
is not fully understood; however, some pulmonary
vessels, in this case a small pulmonary artery ~200
um in diameter, exhibit structural interactions
known as myoendothelial junctions (*) between
endothelial and smooth muscle layers.
Function of pulmonary endothelium
Normal control of pulmonary vasculature
PHT is a predictor of mortality in systolic HF
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Abramson, 1992
108 pts, all CCF
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Mean EF 17%
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Echocardiographic
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N= 80
N= 28
TR velocity
Ventricular indices
FU of 28 months
Abramson et al, Annals of Int Med,1992;116:88-995
Mortality study in HFpEF
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Lam et al, JACC 2009; 53: 1119-26
Echocardiographic derived PASP and PCWP
719 patients with HT as control
244 patients with HFpEF
FU 3 years
PASP predicts mortality in HFpEF
Lam et al, JACC 2009; 53: 1119-26
PHT and Exercise performance
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EF correlates poorly with exercise capacity in HF
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Butler et al, JACC 1999; 34 (6): 1802 – 06
320 patients for Tx workup
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Butler et al. JACC 1999 ; 34, No. 6, :1802–6
Two types of PHT
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Pulmonary arterial hypertension (PAH)
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Group 1 WHO classification
Pulmonary venous hypertension (PVH)
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Group 2 WHO classification
Conceptually seen as
 Pre-capillary
 Post-capillary
Dadfarmay et al Congestive Heart Failure, 2010; 16:287 -291
Post Capillary PHT
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Consequence of
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LV dysfx
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diastolic > systolic
Mitral valve disease
Decreased relaxation and
compliance of LV
Elevated LV filling pressures
Transmitted back to pulmonary
capillaries
Normally remediable to
vasodilators
Definition PVH
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mPAP > 25mmHg
PCWP > 15
Transpulmonary gradient (mPAP – PCWP) <10mmHg
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Two different haemodynamic phenotypes
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1st phenotype of PVH
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Passive retrograde transmission of elevated PCWP into
pulmonary venous system
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Mild increase in upstream PAP
PAP increases only enough to overcome PCWP to maintain
forward flow
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TPG remains <10mmHg
In contrast to PAH, where TPG >10mmHg
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PHT resolves with treatment of LV dysfx
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1st phenotype
Rich and Rabinovitch Circulation 2008;118;2190-2199
2nd phenotype of PVH
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Reactive changes in pulmonary vasculature out of context
of raised PCWP
Smooth muscle and vaso-proliferative changes in the
pulmonary arterioles
Obliterative arteriopathy mediated by endothelin
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TPG >10mmHg
PCWP >15mmHg
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PAP does not normalise with Rx of LV dysfx
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2nd phenotype
Rich and Rabinovitch Circulation 2008;118;2190-2199
Reactive PVH
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More strongly associated with diastolic dysfunction than
systolic dysfunction
Prospective echo study Enriquez-Sarano et al 1997
102 consecutive patients with CCF and EF < 50%
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Strongest correlation with PHT were
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Mitral deceleration time < 150msec (OR 48.8)
Mitral ERO >20mm2 (OR 5.9)
No correlation with
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EF%
LVESV
Enriques-Sarano et al, JACC 1997;29:153–9
Vascular hypertrophy
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Delgado et al, EJHF 2005; 7: 1011–1016
Study of 17 HT recipients with preoperative CHF who
died shortly ( 2.01+/- 2.0 m ) post HTx.
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Haemodynamic data were correlated with the
morphologic changes seen in pulmonary arteries on
autopsy examination
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Correlation, albeit low (r=0.30), of medial thickness to
preTx Transpulmonary gradient
Medial hypertrophy
Pathophysiological paradigm
Moraes, et al. Circulation 2000;102:1718 - 1723
Nitric oxide
Impaired NO-dependent pulmonary
vasodilatation if HF
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Animal models
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Ontkean et al, Circulation Research 1991;69:1088-1096
Enhanced vasoconstriction and diminished vasodilatation in PA
cf. TA of heart failure rat model compared to control
Acetylcholine
response
Enhanced vasoconstriction in PA
Ontkean et al, Circulation Research 1991;69:1088-1096
Human studies
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Cooper et al, Am J Cardiol 1998;82:609–614
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25 patients under went L&R catheterisation
Methods
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Doppler wire in left lower pulmonary artery
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Sequential infusions into PA of
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Phenylephrine at 10-7mol/L
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L-NMMA at 3x10-5 and 6x10-5 mol/L
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With 5% dextrose for 10 mins as interval wash out between
each drug
L-NMMA
Blunted vaso-constriction
Cooper et al, Am J Cardiol 1998;82:609–614
Phenylephrine
Cooper et al, Am J Cardiol 1998;82:609–614
Regarding NO
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Locally produced vaso-dilating factor
Blunted response to NO in CCF
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Especially at raised PVR
Endothelin-1 (ET1)
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Vasoactive peptide first discovered in 1988
CsA, cyclosporin A; EGF, epidermal growth factor; HGF, hepatocyte growth factor;
IL-1, interleukin-1; LDL, low-density lipoprotein; VEGF, vascular endothelial growth
factor.
Remuzzi, Perico and Benigni, Nature Reviews Drug Discovery 1, 986-1001 (December
2002)
Biological Actions of Endothelin
Biological Actions of Endothelin
ET1
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2 receptor subtypes ETA and ETB
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Ratio of A to B is 9:1 in pulmonary vasculature
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ET1 cleared in the lungs
Clearance is mediated by ETB
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ET 1 clearance
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ETB is down regulated in failing myocardium
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Zolk at el, Circulation 1999; 99(16) 2118 -33
DCM n= 11
NF n= 9
Raised ET1 levels in CCF
CCF (n=20) vs.
controls (n = 8)
ET levels related to
1.
Heart rate
2.
PAP
3.
RAP
4.
PVR
Not related to
Cody et al, Circulation 1992;85(2):504-509
1.
MAP
2.
SVR
3.
PCWP
4.
CI or SV
Big ET predicts mortality
•218 patient on HTx waiting list
•Compared ET levels to survival
Hulsman et al J Am Coll Cardiol 1998;32:1695–700
As do other vaso-active peptides
No relationship between VO2max and survival
Hulsman et al J Am Coll Cardiol 1998;32:1695–700
ET related to reduced exercise capacity
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Krum et al, AJC 1995; 75(17):1284 – 86
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12 male patients, mean EF 16% (8 -34%)
10 control patients (9 men, 1 woman)
Bicycle ergometer, cardiopulmonary capacity
However...
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Are these factors (NO and ET1) mediators or markers?
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Therapeutic interventions aimed at ET1 antagonism and
NO augmentation have attempted to address this
Inhaled NO at rest
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Loh et al, Circulation 1994; 90(6): 2780 – 85
19 pts with class III-IV CCF
10 mins of NO at 80ppm
Increased PCWP
Loh et al, Circulation 1994; 90(6): 2780 – 85
No change in CI
Loh et al, Circulation 1994; 90(6): 2780 – 85
NO during exercise testing
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Koelling AJC 1998;81 (12): 1494 – 97
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14 pts undergoing HTx evaluation (Class III-IV)
Bicycle CPX, radionuclear ventriculography, and cardiac
catheterisation
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Rest study as baseline
All repeated whilst breathing 40ppm NO.
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Except cardiac catheterisation
Koelling AJC 1998;81 (12): 1494 – 97
Regarding NO augmentation
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Most benefit in those with worse disease
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Cumbersome to deliver inhaled NO
Endothelin Receptor Antagonists
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Demonstrated benefit in PAH
Promising evidence in animal studies of ischaemic HF
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REACH – 1 – bosentan in CCF
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Pilot study
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ENABLE 1 and 2 bosentan in lower doses
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EARTH – darusentan in CCF
REACH – 1 – bosentan in CCF
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Packer et al, Journal of Cardiac Failure Vol. 11 No. 1 2005
Pilot, dose finding study
N= 370 pts with CCF
Placebo (N= 126)
Vs
Bosentan slow titration (N= 121)
 Bosentan fast titration (N =123)
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to a target dose of 500 mg twice daily
Baffle me with Bull....
Packer et al, Journal of Cardiac Failure Vol. 11 No. 1 2005
However...
Hospitalisation or drug discontinuation
P = not given
Death or worsening heart failure
P = not given
Packer et al, Journal of Cardiac Failure Vol. 11 No. 1 2005
Less death at lower dose of Bosentan
Packer et al, Journal of Cardiac Failure Vol. 11 No. 1 2005
ENABLE- Endothelin Antagonist Bosentan
for Lowering Cardiac Events
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N= 1613 patients
Bosentan 125 mg twice a day vs placebo.
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1° endpoint - All-cause mortality or hospitalization for heart
failure
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1° endpoint 321/808 patients on placebo
1° endpoint 312/805 receiving bosentan.
HR 1.01 (P = 0.9)
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Treatment with bosentan appeared to confer an early risk of
worsening heart failure necessitating hospitalization, as a
consequence of fluid retention.
51st Annual Scientific Session of the American College of Cardiology (17–20 March 2002, Atlanta, GA, USA).
EARTH – Darusentan in CCF
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Selective ET-A antagonist
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N = 642 patients with chronic heart failure
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50, 100, or 300 mg Darusentan daily or placebo
Duration 24 weeks
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Primary end point = change in LVESV assessed by Cardiac
MRI
Secondary end points = 6MWT, QoL, plasma levels of ET,
Norad, ANP, aldosterone, ADP
EARTH
Anand et al, Lancet 2004; 364: 347–54
No significant change in anything
Anand et al, Lancet 2004; 364: 347–54
Summary
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Pulmonary hypertension is an adverse pathological
marker
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Occurs in both in systolic HF and diastolic HF
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NO and ET1 are key hormones involved in the
pathogenesis of this phenomenon
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Therapy aimed at augmenting or ameliorating these
factors has yet to reveal any significant benefit
Bibliography
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Abramson et al. Pulmonary Hypertension Predicts Mortality and Morbidity in Patients with Dilated Cardiomyopathy, Annals of Internal medicine ,
1992;116:888-995
Lam et al, Pulmonary Hypertension in Heart failure with preserved ejection fraction: a Community based Study JACC 2009; 53: 1119-26
Butler J et al, Pulmonary hypertension and exercise intolerance in patients with heart failure, J. Am. Coll. Cardiol 1999;34:1802 -1806
Dadfarmay et al, Differentiating Pulmonary Arterial and Pulmonary Venous Hypertension and Implications for Therapy, Congestive Heart Failure,
2010; 16:287 -291
Rich and Rabinovitch, Diagnosis and Treatment of Secondary (Non-Category 1) Pulmonary Hypertension, Circulation 2008;118;2190-2199
Enriques-Sarano, M, Determinants of Pulmonary Hypertension in Left Ventricular Dysfunction, JACC 1997;29:153–9
Delgado et al, Pulmonary Vascular Remodelling in pulmonary hypertension due to chronic heart failure, European J Heart Failure 2005; 7: 1011–1016
Moraes et al, Secondary Pulmonary Hypertension in Chronic Heart Failure The Role of the Endothelium in Pathophysiology and Management,
Circulation 2000;102:1718 – 1723
Ontkean et al, Diminished Endothelium-Derived Relaxing Factor Activity in an Experimental Model of Chronic Heart Failure, Circulation Research
1991;69:1088-1096
Cooper et al, The Influence of Basal Nitric Oxide Activity on Pulmonary Vascular Resistance in Patients With Congestive Heart Failure, Am J Cardiol
1998;82:609–614
Remuzzi, Perico and Benigni, Endothelin and related Peptides Nature Reviews Drug Discovery 1, 986-1001 (December 2002)
Zolk at el, Expression of Endothelin-1, Endothelin-Converting Enzyme, and Endothelin Receptors in Chronic Heart Failure, Circulation 1999; 99(16)
2118 -33
Cody et al, Plasma Endothelin Correlates With the Extent of Pulmonary Hypertension in Patients With Chronic Congestive Heart Failure, Circulation
1992;85(2):504-509
Hulsman et al, Value of Cardiopulmonary Exercise Testing and Big Endothelin Plasma Levels to Predict Short-Term Prognosis of Patients With
Chronic Heart Failure, J Am Coll Cardiol 1998;32:1695–700
Krum et al, Role of Endothelin in the Exercise Intolerance of Chronic Heart Failure , Am.J.Cardiol 1995; 75(17):1284 – 86
Loh et al, Cardiovascular effects of inhaled nitric oxide in patients with left ventricular dysfunction, Circulation 1994; 90(6): 2780 – 85
Koelling et al, Inhaled Nitric Oxide Improves Exercise Capacity in Patients With Severe Heart Failure and Right Ventricular Dysfunction, Am J. Cardiol
1998;81 (12): 1494 – 97
Packer et al,
ENABLE trial group, Endothelin Antagonist Bosentan for Lowering Cardiac Events 51st Annual Scientific Session of the American College of
Cardiology (17–20 March 2002, Atlanta, GA, USA).
Anand et al, Long-term effects of darusentan on left-ventricular remodelling and clinical outcomes in the Endothelin-A Receptor Antagonist Trial in
Heart Failure (EARTH): randomised, double-blind, placebo-controlled trial, Lancet 2004; 364: 347–54