22.06.2013 Ideal risk prognosticator � Easy to acquire � Safe -- Non-invasive Non-Invasive Risk Predictors in (Children with) Pulmonary Hypertension � Robust � High sensitivity and specificity Gerhard-Paul Diller Astrid Lammers � Cost effective 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 Non-invasive risk predictors Risk factor � A variable that is quantitatively associated with a � Aetiology of PH disease or other outcome & modification of the risk � Demographics factor may alter the risk of the outcome � Symptoms / functional class � Vital signs Risk marker � Exercise capacity (6-MWTd, CPET) � A variable that is associated with a disease or other � Imaging (Echocardiography, MRI) outcome, but modification of the marker does not � Biomarkers necessarily alter the risk of the outcome � Autonomic dysfunction 1
22.06.2013 Non-invasive risk predictors � Aetiology of PH � Demographics � Symptoms / functional class � Vital signs � Exercise capacity (6-MWTd, CPET) � Imaging (Echocardiography, MRI) � Biomarkers � Autonomic dysfunction Simonneau G, JACC 2009 Survival curves for subgroups in paediatric associated PAH Survival curves for the subgroups of PH Dutch Registy GOSH London Van Loon RL. Circulation 2011;124:1755-1764. Haworth S G , and Hislop A Heart 2009;95:312-317 McLaughlin VV, Chest 2004 2
22.06.2013 Non-invasive risk predictors Demographics and Comorbidities � Aetiology of PH � Demographics � Symptoms / functional class � Vital signs � Exercise capacity (6-MWTd, CPET) � Imaging (Echocardiography, MRI) � Biomarkers � Autonomic dysfunction Benza RL. Circulation 2010; 121: 164-172. REVEAL Registry – Paediatric Patients (n=216) Non-invasive risk predictors � Aetiology of PH � Demographics � Symptoms / functional class � Vital signs � Exercise capacity (6-MWTd, CPET) � Imaging (Echocardiography, MRI) � Biomarkers � Autonomic dysfunction Barst RJ. Circulation 2012; 125: 113-122. 3
22.06.2013 Functional class at baseline – Impact on Prognosis Change in Functional classification – Impact on Prognosis McLaughlin VV. Circulation 2002;106:1477-82. Barst RJ. Chest 2013 Functional classification of pulmonary hypertension in children: Report from the PVRI pediatric taskforce, Panama 2011 Non-invasive risk predictors Pediatric functional classification for children aged 0–0.5 years � Aetiology of PH � Demographics � Symptoms / functional class � Vital signs Pediatric functional classification for children aged 2–5 years � Exercise capacity (6-MWTd, CPET) � Imaging (Echocardiography, MRI) � Biomarkers � Autonomic dysfunction Lammers AE. Pulm Circ. 2011; 1(2): 280–285. 4
22.06.2013 Predictive Value of SBP and HR in REVEAL Non-invasive risk predictors � Aetiology of PH � Demographics � Symptoms / functional class � Vital signs � Exercise capacity (6-MWTd, CPET) � Imaging (Echocardiography, MRI) � Biomarkers � Autonomic dysfunction Bersohn MM. Chest 2013 Relationship between ∆ 6-MWTd and Outcome Prognostic Value of 6-minute walk test distance (IPAH) Death Comp. outcome Meta-Regression>3,000 patients Conclusion - In patients with PAH, improvement in 6MWD does not reflect benefit in clinical outcomes. Hosp. PAH/Tx Rescue therapy 6-MWTd maybe a risk marker rather than a risk factor. Miyamoto S. AJRCCM 2000 19 Savarese G. JACC 2012;60:1192-201. 5
22.06.2013 Six-minute walk test distance versus peak VO 2 (CPET) Increase of 6MWT distance with age in healthy children Submaximal vs . maximal exercise test Confounding effect of maturation Lammers et al, Arch Dis Child. 2007 Lammers et al, Arch Dis Child. 2007 Peak oxygen uptake - CPET Non-invasive risk predictors � Aetiology of PH � Demographics � Symptoms / functional class � Vital signs � Exercise capacity (6-MWTd, CPET) � Imaging (Echocardiography, MRI) � Biomarkers � Autonomic dysfunction 23 Wensel R. Circulation 2002 6
22.06.2013 “ 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. “ RV Function – Tei Index / TAPSE Estimate RV Function a b Tricuspid annular plane systolic Myocarial performance index excursion – TAPSE normal > 16 mm normal > 0.28 mm Am J Cardiol. 2012 Sep 15;110(6 Suppl):16S-24S. 27 Yeo TC et al. Am J Cardiol 1998; 81: 1157-1161 7
22.06.2013 Prognostic Value in specific PAH groups iPAH vs. Eisenmenger-Syndrome Example: Eisenmenger syndrome Mean age 39 ± ± ± 13 years ± 181 pts. Systole Diastole Median FU 16 months 19 deaths iPAH 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 Eisenmenger S. approx 40% of patients – non predictive Confirmed by Van De Bruaene A (IJC 2012) – 77 Eisenmenger pts. TAPSE pred. ouf outcome Diller et al., EHJ 2007 Mocieri P. Circulation. 2012;126:1461-8. Other important aspects 8
22.06.2013 Non-invasive risk predictors � Aetiology of PH � Demographics � Symptoms / functional class � Vital signs � Exercise capacity (6-MWTd, CPET) � Imaging (Echocardiography, MRI) � Biomarkers � Autonomic dysfunction Moledina S et al. Circ Cardiovasc Imaging 2013;6:407-414 BNP as a Predictor of Mortality in Pulmonary Arterial Brain natriuretic peptide Hypertension NT-pro BNP independent predictor of death on univariate and multivariate analysis, BNP only predicted mortality on univariate analysis. Diller GP. Heart. 2012;98:736-42. Leuchte HH. Chest 2007; 131:402-409. 9
22.06.2013 Brain natriuretic peptide Brain natriuretic peptide Diller GP. Heart. 2012;98:736-42. Diller GP. Heart. 2012;98:736-42. Prognostic value of BNP in children with PH Prognostic value of BNP in children with PH IPAH : Sensitivity 47.4% Specitivity 90% Lammers et al, Int J Cardiol. 2009;135:21-6. Lammers et al, Int J Cardiol. 2009;135:21-6. 10
22.06.2013 Prognostic value of BNP in children with PH Non-invasive risk predictors � Aetiology of PH � Demographics � Symptoms / functional class � Vital signs � Exercise capacity (6-MWTd, CPET) � Imaging (Echocardiography, MRI) � Biomarkers � Autonomic dysfunction Lammers et al, Int J Cardiol. 2009;135:21-6. Autonomic dysfunction – Arrhythmias Parameters of HRV Mode of Death in Patients with Eisenmenger Syndrome – SDNN – standard deviation of normal-to-normal intervals – SDANN – stand. dev. of mean Right Ventricular Failure values for normal-to-normal Sudden Cardiac Death intervals in all 5‘ -segments CVS Surgery CVA/Abscess – RMSSD – square root of the mean squared differences of successive Haemoptysis RR intervals Extracardiac Surgery Transplantation 0 5 10 15 47 children with PHT (21 IPAH) mean 11.4+5.5 years Somerville J, Int J Cardiol. 1998 ;63:1-8. Lammers A, Int J Cardiol. 2010;142(2):159-65. 11
22.06.2013 Autonomic dysfunction – Arrhythmias The blind monks Parameters of HRV IPAH: Sensitivity 90%, Specifitivity 72.7% Lammers A, Int J Cardiol. 2010;142(2):159-65. REVEAL Registry Risk Score Guiding Therapy – Assessing Prognosis Age 53 ± ± ± 17 years ± Validation cohort: 504 pts. N. Galie et al., ESC Guidelines for the diagnosis and treatment of pulmonary, Eur Heart J, 30 (2009) 2493-2537. 47 Benza RL. Chest 2012; 141: 354-362. 12
22.06.2013 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 Thank you ! � 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 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 Backup slides 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. 13
22.06.2013 REVEAL Registry Risk Score Guiding Therapy – Assessing Prognosis V.V. McLaughlinet al., ACCF/AHA 2009 expert consensus document on pulmonary hypertension, Circulation, 119 (2009) 2250-2294. Benza RL. Chest 2012; 141: 354-362. Combining Parameters Useful N. Galie et al Eur Heart J, 30 (2009) 2493-2537. V.V. McLaughlinet al., Circulation, 119 (2009) 2250-2294. 56 Howard LS. Eur Resp Rev. 2012 14
22.06.2013 Interventricular Interaction – LV Form and Function Load Dependence 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. 57 58 Functional classification - Syncope RV Mikhail GW, Circulation. 2001 ;104:1326-7 15
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