22.06.2013

1

Non-Invasive Risk Predictors in (Children with) Pulmonary Hypertension

Gerhard-Paul Diller

Astrid Lammers

Division of Adult Congenital and Valvular Heart Disease, Department of Cardiovascular Medicine, University Hospital Muenster, Germany

National Heart Institute, Imperial College of Science and Medicine and the Royal Brompton Hospital, London, UK

Ideal risk prognosticator

� Easy to acquire

� Safe -- Non-invasive

� Robust

� High sensitivity and specificity

� Cost effective

Risk factor

� A variable that is quantitatively associated with a disease or other outcome & modification of the risk factor may alter the risk of the outcome

Risk marker

� A variable that is associated with a disease or other outcome, but modification of the marker does not necessarily alter the risk of the outcome

Non-invasive risk predictors

� Aetiology of PH

� Demographics

� Symptoms / functional class

� Vital signs

� Exercise capacity (6-MWTd, CPET)

� Imaging (Echocardiography, MRI)

� Biomarkers

� Autonomic dysfunction

22.06.2013

2

Non-invasive risk predictors

� Aetiology of PH

� Demographics

� Symptoms / functional class

� Vital signs

� Exercise capacity (6-MWTd, CPET)

� Imaging (Echocardiography, MRI)

� Biomarkers

� Autonomic dysfunction

Simonneau G, JACC 2009

McLaughlin VV, Chest 2004

Survival curves for the subgroups of PH Survival curves for subgroups in paediatric associa ted PAH

Van Loon RL. Circulation 2011;124:1755-1764.Haworth S G , and Hislop A Heart 2009;95:312-317

Dutch Registy GOSH London

22.06.2013

3

Non-invasive risk predictors

� Aetiology of PH

� Demographics

� Symptoms / functional class

� Vital signs

� Exercise capacity (6-MWTd, CPET)

� Imaging (Echocardiography, MRI)

� Biomarkers

� Autonomic dysfunction

Demographics and Comorbidities

Benza RL. Circulation 2010; 121: 164-172.

REVEAL Registry – Paediatric Patients (n=216)

Barst RJ. Circulation 2012; 125: 113-122.

Non-invasive risk predictors

� Aetiology of PH

� Demographics

� Symptoms / functional class

� Vital signs

� Exercise capacity (6-MWTd, CPET)

� Imaging (Echocardiography, MRI)

� Biomarkers

� Autonomic dysfunction

22.06.2013

4

Functional class at baseline – Impact on Prognosis

McLaughlin VV. Circulation 2002;106:1477-82.

Change in Functional classification – Impact on Prog nosis

Barst RJ. Chest 2013

Pediatric functional classification for children ag ed 0–0.5 years

Pediatric functional classification for children ag ed 2–5 years

Functional classification of pulmonary hypertension in children: Report from the PVRI pediatric taskforce, Panama 20 11

Lammers AE. Pulm Circ. 2011; 1(2): 280–285.

Non-invasive risk predictors

� Aetiology of PH

� Demographics

� Symptoms / functional class

� Vital signs

� Exercise capacity (6-MWTd, CPET)

� Imaging (Echocardiography, MRI)

� Biomarkers

� Autonomic dysfunction

22.06.2013

5

Predictive Value of SBP and HR in REVEAL

Bersohn MM. Chest 2013

Non-invasive risk predictors

� Aetiology of PH

� Demographics

� Symptoms / functional class

� Vital signs

� Exercise capacity (6-MWTd, CPET)

� Imaging (Echocardiography, MRI)

� Biomarkers

� Autonomic dysfunction

Prognostic Value of 6-minute walk test distance (IP AH)

19Miyamoto S. AJRCCM 2000

Relationship between ∆ 6-MWTd and Outcome

Savarese G. JACC 2012;60:1192-201.

Comp. outcome Death

Hosp. PAH/Tx Rescue therapy

Meta-Regression>3,000 patients

Conclusion - In patients with PAH, improvement in 6MWD does not reflect benefit in clinical outcomes.

6-MWTd maybe a risk marker rather than a risk factor.

22.06.2013

6

Six-minute walk test distance versus peak VO 2 (CPET)Submaximal vs . maximal exercise test

Lammers et al, Arch Dis Child. 2007

Increase of 6MWT distance with age in healthy child renConfounding effect of maturation

Lammers et al, Arch Dis Child. 2007

Peak oxygen uptake - CPET

23Wensel R. Circulation 2002

Non-invasive risk predictors

� Aetiology of PH

� Demographics

� Symptoms / functional class

� Vital signs

� Exercise capacity (6-MWTd, CPET)

� Imaging (Echocardiography, MRI)

� Biomarkers

� Autonomic dysfunction

22.06.2013

7

“ It is the integrity of right ventricular function, ratherthan the degree of vascular injury, that is the major

determinant of symptoms and survival in PAH. “

Estimate RV Function

27

Tricuspid annular plane systolicexcursion – TAPSE normal > 16 mm

Myocarial performance indexnormal > 0.28 mm

b

a

Yeo TC et al. Am J Cardiol 1998; 81: 1157-1161

RV Function – Tei Index / TAPSE

Am J Cardiol. 2012 Sep 15;110(6 Suppl):16S-24S.

22.06.2013

8

Prognostic Value in specific PAH groupsExample: Eisenmenger syndrome

Mocieri P. Circulation. 2012;126:1461-8.

181 pts. Mean age 39±±±±13 yearsMedian FU 16 months19 deaths

Predictors:TAPSE <15 mm,RV eff. syt. to diast. duration >1.5RA area >25 cm2,ratio of RA to left atrial area >1.5

Pericardial effusion commonapprox 40% of patients –non predictive

Confirmed by Van De Bruaene A (IJC 2012) – 77 Eisenmenger pts. TAPSE pred. ouf outcome

iPAH vs. Eisenmenger-Syndrome

SystoleDiastole

iPAH

Eisenmenger S.

Diller et al., EHJ 2007

Other important aspects

22.06.2013

9

Moledina S et al. Circ Cardiovasc Imaging 2013;6:407-414

Non-invasive risk predictors

� Aetiology of PH

� Demographics

� Symptoms / functional class

� Vital signs

� Exercise capacity (6-MWTd, CPET)

� Imaging (Echocardiography, MRI)

� Biomarkers

� Autonomic dysfunction

NT-pro BNP independent predictor of death on univariate andmultivariate analysis, BNP only predicted mortality on univariate

analysis.

Leuchte HH. Chest 2007; 131:402-409.

BNP as a Predictor of Mortality in Pulmonary Arteri al Hypertension

Brain natriuretic peptide

Diller GP. Heart. 2012;98:736-42.

22.06.2013

10

Brain natriuretic peptide

Diller GP. Heart. 2012;98:736-42.

Brain natriuretic peptide

Diller GP. Heart. 2012;98:736-42.

Lammers et al, Int J Cardiol. 2009;135:21-6.

Prognostic value of BNP in children with PH

IPAH : Sensitivity 47.4% Specitivity 90%

Prognostic value of BNP in children with PH

Lammers et al, Int J Cardiol. 2009;135:21-6.

22.06.2013

11

Prognostic value of BNP in children with PH

Lammers et al, Int J Cardiol. 2009;135:21-6.

Non-invasive risk predictors

� Aetiology of PH

� Demographics

� Symptoms / functional class

� Vital signs

� Exercise capacity (6-MWTd, CPET)

� Imaging (Echocardiography, MRI)

� Biomarkers

� Autonomic dysfunction

0 5 10 15Transplantation

Extracardiac SurgeryHaemoptysis

CVA/AbscessCVS Surgery

Sudden Cardiac DeathRight Ventricular Failure

Somerville J, Int J Cardiol. 1998 ;63:1-8.

Mode of Death in Patients withEisenmenger Syndrome

Autonomic dysfunction – ArrhythmiasParameters of HRV

– SDNN – standard deviation ofnormal-to-normal intervals

– SDANN – stand. dev. of meanvalues for normal-to-normal intervals in all 5‘ -segments

– RMSSD – square root of the meansquared differences of successiveRR intervals

Lammers A, Int J Cardiol. 2010;142(2):159-65.

47 children with PHT (21 IPAH)mean 11.4+5.5 years

22.06.2013

12

IPAH: Sensitivity 90%, Specifitivity 72.7%

Autonomic dysfunction – ArrhythmiasParameters of HRV

Lammers A, Int J Cardiol. 2010;142(2):159-65.

The blind monks

Guiding Therapy – Assessing Prognosis

47N. Galie et al., ESC Guidelines for the diagnosis and treatm ent of pulmonary, Eur Heart J, 30 (2009) 2493-2537.

REVEAL Registry Risk Score

Benza RL. Chest 2012; 141: 354-362.

Validation cohort: 504 pts.Age 53±±±±17 years

22.06.2013

13

Conclusion

� Multiple non-invasive risk predictors suggested

� Most perform reasonable well in the derivation sample

� Lack of external validation and assessment of

incremental prognosticc value

� Integrating the results of repeated tests into a

prognostic score challenging

� Non-invasive risk markers should not be seen in

isolation

� Ultimately, good clinical judgement and experience

required

Thank you !

Backup slides

Usefulness of BNP as a Predictor of Treatment Outcome in Pulmonary Arterial Hypertension

� A decrease in BNP level of >50% during the first 3 months on epoprostenol was strongly predictive of event-free survival (p=0.003).

� This investigation establishes the utility of BNP for predicting response to epoprostenol therapy in pulmonary arterial hypertension.

Park MH et al. Congest Heart Fail. 2004;10(5):221-5.

22.06.2013

14

V.V. McLaughlinet al., ACCF/AHA 2009 expert consensus documen t on pulmonary hypertension, Circulation, 119 (2009) 2250-2294.

Guiding Therapy – Assessing PrognosisREVEAL Registry Risk Score

Benza RL. Chest 2012; 141: 354-362.

Combining Parameters Useful

56

N. Galie et al Eur Heart J, 30 (2009) 2493-2537.V.V. McLaughlinet al., Circulation, 119 (2009) 2250- 2294.

Howard LS. Eur Resp Rev. 2012

22.06.2013

15

Interventricular Interaction – LV Form and Function

57

Louie EK et al., Doppler echocardiographic demonstration of the differential effects of right ventricular pressureand volume overload on left ventricular geometry and filling. J Am Coll Cardiol 1992;19:84-90.

Load Dependence

58

Mikhail GW, Circulation. 2001 ;104:1326-7

RV

Functional classification - Syncope