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Pulmonary hypertension in LV dysfunction

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

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Pulmonary hypertension in LV dysfunction

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  1. Pulmonary hypertension in LV dysfunction Dr Angela Worthington April 5th 2011

  2. Overview • Normal pulmonary physiology • Pathophysiology • Clinical research • Therapeutic trials

  3. 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

  4. 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

  5. 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.

  6. Function of pulmonary endothelium

  7. Normal control of pulmonary vasculature

  8. 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 months N= 80 N= 28 Abramson et al, Annals of Int Med,1992;116:88-995

  9. 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

  10. PASP predicts mortality in HFpEF Lam et al, JACC 2009; 53: 1119-26

  11. 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

  12. Butler et al. JACC 1999 ; 34, No. 6, :1802–6

  13. 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

  14. 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

  15. Definition PVH • mPAP > 25mmHg • PCWP > 15 • Transpulmonary gradient (mPAP – PCWP) <10mmHg • Two different haemodynamic phenotypes

  16. 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

  17. 1st phenotype Rich and Rabinovitch Circulation 2008;118;2190-2199

  18. 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

  19. 2nd phenotype Rich and Rabinovitch Circulation 2008;118;2190-2199

  20. 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

  21. Enriques-Sarano et al, JACC 1997;29:153–9

  22. 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

  23. Medial hypertrophy

  24. Pathophysiological paradigm Moraes, et al. Circulation 2000;102:1718 - 1723

  25. Nitric oxide

  26. 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

  27. Enhanced vasoconstriction in PA • Ontkean et al, Circulation Research 1991;69:1088-1096

  28. Human studies • Cooper et al, Am J Cardiol 1998;82:609–614 • 25 patients under went L&R catheterisation

  29. 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

  30. L-NMMA Blunted vaso-constriction Cooper et al, Am J Cardiol 1998;82:609–614

  31. Phenylephrine Cooper et al, Am J Cardiol 1998;82:609–614

  32. Regarding NO • Locally produced vaso-dilating factor • Blunted response to NO in CCF • Especially at raised PVR

  33. 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)

  34. Biological Actions of Endothelin

  35. Biological Actions of Endothelin

  36. 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

  37. ET 1 clearance • ETB is down regulated in failing myocardium • Zolk at el, Circulation 1999; 99(16) 2118 -33 DCM n= 11 NF n= 9

  38. Raised ET1 levels in CCF CCF (n=20) vs. controls (n = 8) ET levels related to Heart rate PAP RAP PVR Not related to MAP SVR PCWP CI or SV Cody et al, Circulation 1992;85(2):504-509

  39. 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

  40. As do other vaso-active peptides No relationship between VO2max and survival Hulsman et al J Am Coll Cardiol 1998;32:1695–700

  41. 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

  42. However... • Are these factors (NO and ET1) mediators or markers? • Therapeutic interventions aimed at ET1 antagonism and NO augmentation have attempted to address this

  43. 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

  44. Increased PCWP Loh et al, Circulation 1994; 90(6): 2780 – 85

  45. No change in CI Loh et al, Circulation 1994; 90(6): 2780 – 85

  46. 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

  47. Koelling AJC 1998;81 (12): 1494 – 97

  48. Regarding NO augmentation • Most benefit in those with worse disease • Cumbersome to deliver inhaled NO

  49. 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

  50. 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

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