3rd Pan-American Thalassaemia Conference Buenos Aires 2010 Dr Malcolm Walker Cardiologist University College & the Heart Hospital LONDON Clinical Director Hatter Cardiovascular Institute - UCLH PULMONARY HYPERTENSION & THALASSAEMIA
Pulmonary hypertension & the haemoglobinopathies Definition Measurement Pathophysiology Consequences Clinical prevalence & implications Treatments
The Circulation Right Heart Low pressure high flow
The Circulation - pressures
Pulmonary hypertension Definition Normal values at rest: Mean pulmonary artery pressure (mpap): = 8 20 mmhg Pulmonary hypertension mpap >25 mmhg
Pulmonary hypertension Measurement Direct Cardiac Catheterisation
Pulmonary hypertension Measurement Direct by cardiac catheterisation Gold Standard Can measure PA pressure & mpa, Cardiac output, saturations, indirect or direct left heart pressures BUT Invasive, with attendant small risk Results may not be representative Patient lying down, fasted, often dehydrated May require provocation test hypoxia, inhaled NO, fluid challenge
Pulmonary hypertension Measurement Direct by cardiac catheterisation Echocardiography
Doppler: tricuspid jet velocity
Correlation of tricuspid jet velocity & invasive measurement Simplified Bernoulli equation: pressure drop = 4 x Vmax 2
Doppler tricuspid jet velocity - advantages ECHO technology widely available Cheap and rapid (instant) Completely safe & painless, so can repeat at any moment, at the bed-side if necessary BUT does NOT measure mpap Gives peak pressure drop between RV & RA Assume systolic pressure in RV = PA To get syspap need to add RA pressure often assumed to be 5 mmhg
Doppler: tricuspid jet velocity Vmax = 2.6 m/s Pres. drop = 4 x (2.6) 2 Pres. drop = 27 mmhg syspap = 27 + RAp; assume 5 mmhg RAp syspap = 33 mmhg
Doppler: tricuspid jet velocity syspap = 33 mmhg BUT mpap = (0.6 x syspap + 2) mmhg mpap = 18 mmhg
Problems with Doppler tricuspid jet velocity Tricuspid jet absent in about 20% Poor indicator of pressure if tricuspid regurgitation (TR) is more than moderate As RV dilates apparent fall in PA pressure may be seen due to increased TR
Problems with Doppler tricuspid jet velocity Conversion from velocity to pressure amplifies errors of velocity (V) measurement (P = 4xV 2 ) RA pressure estimates from 5 to 15 mmhg wildly inaccurate (syspap = P + Rap) To get to mpap: = (syspap x 0.6 + 2) mmhg There is a case to stick to TR jet velocity without conversion to a pressure measurement
Pulmonary hypertension Measurement Conclusions ECHO TR jet velocity: practical tool for screening Cardiac catheterisation: for special circumstances Cardiac Magnetic Resonance imaging : techniques in development
Pulmonary hypertension Pathophysiology The cause of increased mpa Mostly a condition of pulmonary arteries, this is termed pulmonary arterial hypertension PAH Idiopathic & hereditable Associated with connective tissue disease Portal hypertension Congenital heart disease (shunts) Pulmonary hypertension PH may also be a consequence of severe left ventricular disease
Pulmonary hypertension Pathophysiology Whatever the cause of Pulmonary hypertension it results in: Right ventricular failure RV failure causes the symptoms & accounts for the mortality associated with PH
Pulmonary hypertension Pathophysiology Pulmonary arterial pathophysiology
Pulmonary hypertension Pathophysiology Pulmonary arterial hypertension (PAH) Initial reversible vasoconstriction Pulmonary arterial remodelling Thickening of vessel walls due to smooth muscle & fibroblast proliferation + increased extra-cellular matrix Increased vascular stiffness & resistance Increased resistance (PVR)
Pulmonary hypertension Pathophysiology
Pulmonary hypertension Pathophysiology Pulmonary arterial pathophysiology Complex
Pulmonary Hypertension: Etiology Splenectomy Liver Dysfunction Hemolysis Cardiac Output Endothelial Shear Stress Iron Circulating platelet Aggregates Endothelial Dysfunction/Toxicity Angiotoxic mediators or Trophic Factors Arginine NO LA pressure LV compliance Abnormal Mechanical Forces Pulmonary Artery Circumferential Stress + Vasoconstriction = Pulmonary Hypertension Restrictive Lung Disease Hypoxemia Pulmonary Diffusion Block
Pulmonary hypertension Pathophysiology Pulmonary arterial pathophysiology Complex
Pulmonary hypertension Pathophysiology Pulmonary arterial pathophysiology Complex Main target for therapy Right Ventricular adaptation & failure Poorly studied It is main cause of symptoms/ mortality in PH Measurement of RV function is difficult
Pulmonary hypertension Haemoglobinopathies are prime candidates for the development of PH : Release of free Hb from haemolysis (NO) Hypoxia Increased shear stress via high cardiac output Thrombosis
Pulmonary hypertension clinical correlates Thalassaemia major (TM) Variable incidence of PH complicating TM Lebanese/ Egypt experience in children TR jet velocity > 2.5 m/s (PAsp 25 mmhg): 12/20 (60%) UK experience (UCLH) Adult clinic population < 5% TR jet velocity > 2.5 m/s Transient PH complicating Left Ventricular failure US report 60% incidence in 1 study Greek experience in HbS Thal Severe PH in 2.9%; Mild PH 27% (TR jet > 2.6 m/s)
Pulmonary hypertension clinical correlates Thalassaemia major (TM) Pulmonary hypertension (TR jet > 2.5 m/s) Uncommon in uncomplicated TM Good chelation Low cardiac iron Good LV function Seen under certain circumstances: Acute LV failure Pulmonary embolism
Pulmonary hypertension in TM
Pulmonary hypertension clinical correlates Thalassaemia major (TM) Pulmonary hypertension Uncommon in uncomplicated TM Good chelation Low cardiac iron Good LV function Seen under certain circumstances: Acute LV failure Pulmonary embolism
Pulmonary hypertension clinical correlates Thalassaemia intermedia (TI) Accepted that much higher incidence of PH Mechanisms might include: 1. Haemolysis free Hb interference with NO 2. Embolism high risk of CTPE splenectomy 3. PAH due to shear stress high CO due to anaemia 4. Poor LV function - uncommon
Pulmonary hypertension clinical correlates All Thalassaemia Definition of PH is lacking Can 2.5m/s (25 mmhg) be accepted? Is 2.9 m/s (34 mmhg) more appropriate? REGULAR Screening by ECHO Doppler now essential Establish if PHT due to poor LV function Assess RV function with great care (difficult, but TDI RV systolic longitudunal velocity is promising) BNP
Pulmonary hypertension clinical plan ECHO shows TR jet velocity > 2.5 m/s Or ECHO shows worsening RV function 1. Establish LV function 2. Exclude pulmonary embolism 3. Assess baseline functional capacity 6 minute walk test distance in m Treadmill test or Cpex if available
Pulmonary hypertension clinical plan ECHO shows TR jet velocity > 2.5 m/s Or ECHO shows worsening RV function 1. Establish LV function 2. Exclude pulmonary embolism 3. Assess baseline functional capacity 6 minute walk test distance in m Treadmill test or Cpex if available
Pulmonary hypertension in thalassamia : treatment 1. Isolated PH with normal LV function 1. Diminish haemolysis 2. Diminish hypoxia, thrombosis, high cardiac output state 3. Drugs 2. PH with impaired LV function 1. Chelate if iron overload is the problem 2. ACEi + beta-blockers (carvidelol) 3. Spironolactone
Pulmonary hypertension in thalassaemia : drugs Drugs: no prospective trial data yet available 1. Warfarin 2. Digoxin 3. Phosphodiesterase inhibitors (PD5) sildenafil (Viagra marketed for PH as Revatio 20 to 80mg tds) 4. Calcium channel blockers: Nifedipine, amlodipine 5. 5 hydroxyurea (raising NO via arginine mechanism) 6. Endothelin receptor antagonists: bosentan, ambrisentan, sitaxentan 7. Thromboxane inhibitors: epoprostenol, iloprost, treprostinil 8. l-carnitine
Pulmonary hypertension in thalassaemia : treatment Drugs costs pa. estimated in US$ 1. Warfarin: 800 2. Digoxin: 50 3. Sildenafil 15,000 4. CCB 500 5. 5 HU 6. ERA bosentan 35,000 7. Thromboxane inhibitors 100,000 8. l-carnitine?50
Conclusions Pulmonary hypertension There remain more questions than answers What level of TR jet velocity? 2.5 m/s, >3.0 m/s? Patients must be screened for this complication ; use ECHO regularly! If detected, do the simple things first: 1. Optimise haematological care 2. Support LV 3. Warfarin, digoxin & vasodilate if pulmonary vascular reactivity +ve 4. STOP SMOKING!! 5. Improve diet 6. Consider the more complex & expensive therapies