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Pulmonary hypertension in LV dysfunction . Dr Angela Worthington April 5 th 2011. Overview. Normal pulmonary physiology Pathophysiology Clinical research Therapeutic trials. The Right Ventricle. RV is thin walled and distensible - PowerPoint PPT Presentation
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Pulmonary hypertension in LV dysfunction
Dr Angela WorthingtonApril 5th 2011
Overview Normal pulmonary physiology Pathophysiology Clinical research Therapeutic trials
The Right Ventricle RV is thin walled and
distensible Significant component of
ejection function comes from bellows effect conferred by negative and positive intra-thoracic pressure.
Normal RV can generate systolic pressures up to 45-50mmHg
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 angiotensin-converting 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 Abramson, 1992 108 pts, all CCF
Mean EF 17%
Echocardiographic TR velocity Ventricular
indices
FU of 28 monthsAbramson et al, Annals of Int Med,1992;116:88-995
N= 28
N= 80
Mortality study in HFpEF 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 EF correlates poorly with exercise capacity in
HF
Butler et al, JACC 1999; 34 (6): 1802 – 06 320 patients for Tx workup
Butler et al. JACC 1999 ; 34, No. 6, :1802–6
Two types of PHT Pulmonary arterial hypertension (PAH)
Group 1 WHO classification Pulmonary venous hypertension (PVH)
Group 2 WHO classification
Conceptually seen as Pre-capillary Post-capillary
Dadfarmay et al Congestive Heart Failure, 2010; 16:287 -291
Post Capillary PHT Consequence of
LV dysfx 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 mPAP > 25mmHg PCWP > 15 Transpulmonary gradient (mPAP – PCWP)
<10mmHg
Two different haemodynamic phenotypes
1st phenotype of PVH Passive retrograde transmission of elevated
PCWP into pulmonary venous system Mild increase in upstream PAP PAP increases only enough to overcome PCWP to
maintain forward flow
TPG remains <10mmHg In contrast to PAH, where TPG >10mmHg
PHT resolves with treatment of LV dysfx
1st phenotype
Rich and Rabinovitch Circulation 2008;118;2190-2199
2nd phenotype of PVH 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
TPG >10mmHg PCWP >15mmHg
PAP does not normalise with Rx of LV dysfx
2nd phenotype
Rich and Rabinovitch Circulation 2008;118;2190-2199
Reactive PVH 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%
Strongest correlation with PHT were Mitral deceleration time < 150msec (OR 48.8) Mitral ERO >20mm2 (OR 5.9)
No correlation with EF% LVESV
Enriques-Sarano et al, JACC 1997;29:153–9
Vascular hypertrophy 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.
Haemodynamic data were correlated with the
morphologic changes seen in pulmonary arteries on autopsy examination
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 Animal models
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 Cooper et al, Am J Cardiol 1998;82:609–614
25 patients under went L&R catheterisation
Methods Doppler wire in left lower pulmonary artery
Sequential infusions into PA of Phenylephrine at 10-7mol/L
L-NMMA at 3x10-5 and 6x10-5 mol/L
With 5% dextrose for 10 mins as interval wash out between each drug
L-NMMA
Cooper et al, Am J Cardiol 1998;82:609–614
Blunted vaso-constriction
Phenylephrine
Cooper et al, Am J Cardiol 1998;82:609–614
Regarding NO Locally produced vaso-dilating factor Blunted response to NO in CCF
Especially at raised PVR
Endothelin-1 (ET1) 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 2 receptor subtypes ETA and ETB
Ratio of A to B is 9:1 in pulmonary vasculature
ET1 cleared in the lungs Clearance is mediated by ETB
ET 1 clearance
ETB is down regulated in failing myocardium Zolk at el, Circulation 1999; 99(16) 2118 -33
NF n= 9DCM n= 11
CCF (n=20) vs. controls (n = 8)ET levels related to 1. Heart rate2. PAP3. RAP4. PVRNot related to5. MAP6. SVR7. PCWP8. CI or SVCody et al, Circulation 1992;85(2):504-509
Raised ET1 levels in CCF
Big ET predicts mortality
Hulsman et al J Am Coll Cardiol 1998;32:1695–700
• 218 patient on HTx waiting list• Compared ET levels to survival
As do other vaso-active peptides
Hulsman et al J Am Coll Cardiol 1998;32:1695–700
No relationship between VO2max and survival
ET related to reduced exercise capacity Krum et al, AJC 1995; 75(17):1284 – 86
12 male patients, mean EF 16% (8 -34%) 10 control patients (9 men, 1 woman)
Bicycle ergometer, cardiopulmonary capacity
However... Are these factors (NO and ET1) mediators or
markers?
Therapeutic interventions aimed at ET1 antagonism and NO augmentation have attempted to address this
Inhaled NO at rest 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 Koelling AJC 1998;81 (12): 1494 – 97
14 pts undergoing HTx evaluation (Class III-IV) Bicycle CPX, radionuclear ventriculography,
and cardiac catheterisation
Rest study as baseline All repeated whilst breathing 40ppm NO.
Except cardiac catheterisation
Koelling AJC 1998;81 (12): 1494 – 97
Regarding NO augmentation Most benefit in those with worse disease
Cumbersome to deliver inhaled NO
Endothelin Receptor Antagonists Demonstrated benefit in PAH Promising evidence in animal studies of
ischaemic HF
REACH – 1 – bosentan in CCF Pilot study
ENABLE 1 and 2 bosentan in lower doses
EARTH – darusentan in CCF
REACH – 1 – bosentan in CCF 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)
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...
P = not given
P = not given
Hospitalisation or drug discontinuation
Death or worsening heart failure
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 N= 1613 patients Bosentan 125 mg twice a day vs placebo.
1° endpoint - All-cause mortality or hospitalization for heart failure
1° endpoint 321/808 patients on placebo 1° endpoint 312/805 receiving bosentan. HR 1.01 (P = 0.9)
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 Selective ET-A antagonist
N = 642 patients with chronic heart failure
50, 100, or 300 mg Darusentan daily or placebo
Duration 24 weeks
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 Pulmonary hypertension is an adverse
pathological marker
Occurs in both in systolic HF and diastolic HF
NO and ET1 are key hormones involved in the pathogenesis of this phenomenon
Therapy aimed at augmenting or ameliorating these factors has yet to reveal any significant benefit
Bibliography 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