PULMONARY HYPERTENSION & THALASSAEMIA

3rd Pan-American Thalassaemia Conference – Buenos Aires 2010

Dr Malcolm Walker Cardiologist University College & the Heart Hospital – LONDON Clinical Director Hatter Cardiovascular Institute - UCLH

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Pulmonary hypertension & the haemoglobinopathies

Definition

Measurement

Pathophysiology

Consequences

Clinical prevalence & implications

Treatments

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The Circulation

Right Heart Low pressure high flow

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The Circulation - pressures

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Pulmonary hypertension Definition

Normal values at rest:

Mean pulmonary artery pressure (mPAP):

= 8 – 20 mmHg

Pulmonary hypertension

mPAP >25 mmHg

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Pulmonary hypertension Measurement – Direct

Cardiac Catheterisation

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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

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Pulmonary hypertension Measurement

Direct by cardiac catheterisation

Echocardiography

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Doppler: tricuspid jet velocity

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Correlation of tricuspid jet velocity & invasive measurement

Simplified Bernoulli equation: pressure drop = 4 x Vmax2

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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

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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

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Doppler: tricuspid jet velocity sysPAP = 33 mmHg BUT mPAP = (0.6 x sysPAP + 2) mmHg mPAP = 18 mmHg

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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

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Problems with Doppler tricuspid jet velocity

Conversion from velocity to pressure amplifies errors of velocity (V) measurement (P = 4xV2)

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

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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

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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

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Pulmonary hypertension Pathophysiology

Pulmonary arterial pathophysiology

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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)

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Pulmonary hypertension Pathophysiology

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Pulmonary hypertension Pathophysiology

Pulmonary arterial pathophysiology

Complex

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Pulmonary Hypertension: Etiology

RestrictiveLung Disease

Cardiac Output

HypoxemiaPulmonary ArteryCircumferential Stress

LV compliance

Iron Circulating plateletAggregates

Splenectomy Liver Dysfunction

Angiotoxic mediators or Trophic Factors

Endothelial Dysfunction/Toxicity

AbnormalMechanicalForces

Vasoconstriction = Pulmonary Hypertension

+

PulmonaryDiffusionBlock

Endothelial Shear Stress

LA pressure

Hemolysis

Arginine

NO

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Pulmonary hypertension Pathophysiology

Pulmonary arterial pathophysiology

Complex

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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

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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

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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)

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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

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Pulmonary hypertension in TM

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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

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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

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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

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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

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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

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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

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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

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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

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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

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