22.06.2013 Ideal risk prognosticator Easy to acquire Safe -- - - PowerPoint PPT Presentation

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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

• utcome, 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

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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 associated PAH

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

Dutch Registy GOSH London

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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

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Functional class at baseline – Impact on Prognosis

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

Change in Functional classification – Impact on Prognosis

Barst RJ. Chest 2013

Pediatric functional classification for children aged 0–0.5 years Pediatric functional classification for children aged 2–5 years

Functional classification of pulmonary hypertension in children: Report from the PVRI pediatric taskforce, Panama 2011

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

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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 (IPAH)

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Miyamoto 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.

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Six-minute walk test distance versus peak VO2 (CPET) Submaximal vs. maximal exercise test

Lammers et al, Arch Dis Child. 2007

Increase of 6MWT distance with age in healthy children Confounding effect of maturation

Lammers et al, Arch Dis Child. 2007

Peak oxygen uptake - CPET

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Wensel 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

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“ It is the integrity of right ventricular function, rather than the degree of vascular injury, that is the major determinant of symptoms and survival in PAH. “

Estimate RV Function

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Tricuspid annular plane systolic excursion – TAPSE normal > 16 mm Myocarial performance index normal > 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.

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Prognostic Value in specific PAH groups Example: Eisenmenger syndrome

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

181 pts. Mean age 39± ± ± ±13 years Median FU 16 months 19 deaths Predictors: TAPSE <15 mm, RV eff. syt. to diast. duration >1.5 RA area >25 cm2, ratio of RA to left atrial area >1.5 Pericardial effusion common approx 40% of patients – non predictive Confirmed by Van De Bruaene A (IJC 2012) – 77 Eisenmenger pts. TAPSE pred. ouf outcome

iPAH vs. Eisenmenger-Syndrome

Systole Diastole iPAH Eisenmenger S.

Diller et al., EHJ 2007

Other important aspects

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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 and multivariate analysis, BNP only predicted mortality on univariate analysis.

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

BNP as a Predictor of Mortality in Pulmonary Arterial Hypertension

Brain natriuretic peptide

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

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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.

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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

5 10 15 Transplantation Extracardiac Surgery Haemoptysis CVA/Abscess CVS Surgery Sudden Cardiac Death Right Ventricular Failure Somerville J, Int J Cardiol. 1998 ;63:1-8.

Mode of Death in Patients with Eisenmenger Syndrome Autonomic dysfunction – Arrhythmias Parameters of HRV

– SDNN – standard deviation of

normal-to-normal intervals

– SDANN – stand. dev. of mean

values for normal-to-normal intervals in all 5‘ -segments

– RMSSD – square root of the mean

squared differences of successive RR intervals

Lammers A, Int J Cardiol. 2010;142(2):159-65. 47 children with PHT (21 IPAH) mean 11.4+5.5 years

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IPAH: Sensitivity 90%, Specifitivity 72.7%

Autonomic dysfunction – Arrhythmias Parameters of HRV

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

The blind monks Guiding Therapy – Assessing Prognosis

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• N. Galie et al., ESC Guidelines for the diagnosis and treatment 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

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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.

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

Guiding Therapy – Assessing Prognosis REVEAL Registry Risk Score

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

Combining Parameters Useful

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• 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

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Interventricular Interaction – LV Form and Function

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

Load Dependence

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

Functional classification - Syncope