pulmonary hypertension in lv dysfunction

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

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


Less death at lower dose of Bosentan


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

pulmonary hypertension in lv dysfunction

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