Conflict Of Interest Grants/Boards: Actelion, Bayer, Bellerophon, - PowerPoint PPT Presentation

3/9/2019 Conflict Of Interest Grants/Boards: Actelion, Bayer, Bellerophon, Boehringer, Inventiva, Roche, Ludwig Boltzmann Mildly elevated PAP and Exercise PH Borderline and Exercise Induced PH Society Horst Olschewski Speaker: Actelion, Boehringer, Chiesi, Menarini, Universitätsklinik für Innere Medizin Mondial, MSD, Novartis Klinische Abteilung für Lungenkrankheiten Graz, Österreich Consultancy: Actelion, Astra Zeneca, Bayer, Boehringer, Chiesi, GSK, Menarini, Novartis Pulmonary Arterial Pressure At Rest Borderline PAP 20 Systematic literature research mean PAP (mmHg) 15 N=1121 healthy subjects 10 RHC at rest and • N=141 patients with PAP <25 mmHg exercise 5 – 31 patients with PAP 21-24 mmHg („borderline PAP“) 0 – 110 patients with PAP < 21 mmHg („normal“) e t s s e A r r r h y y y n e e p g S 0 0 0 i l l o p i a a U 3 5 5 r r • Borderline PAP is associated with u m m - p u < 0 > n s u e E i 3 f n i – Increased age and comorbidities PAP 21-24 = PAP = 14.0 ± 3.3 mmHg – Increased PAP/CO slope „borderline ULN = 20.6 mmHg – Increased mortality PAP“ ULN=upper limit of normal Kovacs et al. Eur Respir J 2009;34:888-894 Kovacs et al. CHEST 2014; 146: 1486-1493 1

3/9/2019 „Borderline PH“ Reduced Survival in Borderline PAP associated with mortality normal PAP borderline PAP • N= 21.727 patients – 97% male (VA) – Median age 65 yr PAP 21-24 mmHg vs. PAP <21 mmHg: – Median PAP 26 mmHg Mortality rate 19 % vs. 4 % /4.4 yr mPAP ≥ 19 mmHg associated with increased mortality Kovacs et al. CHEST 2014; 146: 1486-1493 Maron et al. Circulation 2016; 133:1240-1248 6th WSPH Nice 2018 Hemodynamic Definition • Retrospective + prospective evaluation • PH: previously „≥ 25mmHg“ now – N=392+153 patients „> 20mmHg“ – Follow-up 46 months [22-77] • Mortality • i.e. from 25 down to 21 – according to preset thresholds based on PH • Precapillary PH definition and normal values – PAWP ≤ 15mmHg (HR corrected for age+comorbidities) – Lower normal (up to norm + SD) – PVR ≥ 3 WU (240 dyn s cm -5 ) HR=1 • Isolated postcapillary PH – Upper normal (norm +1 SD to norm +2SD) – PAWP >15 mmHg HR=2.0 [0.9-4.5] – PVR < 3 WU (240 dyn s cm -5 ) – Borderline (21-24 mmHg) • HR=2.4 [1.1-5.0] Combined pre+postcapillary PH – PH (≥25 mmHg) – PAWP >15 mmHg HR=5.1 [2.8-9.1] – PVR ≥ 3 WU (240 dyn s cm -5 ) Simonneau et al. ERJ 2019; 53: 1801913 HR = hazard ratio Douschan et al. AJRCCM 2018;197:509-516 2

3/9/2019 Dependency of PAP from CO Pulmonary Arterial Pressure At Exercise 35 >50 yr 40 30 mean PAP (mmHg) >30-50 yr 25 mean PAP (mmHg) 30 20 <30 yr 15 20 10 5 10 0 0 5 10 15 20 25 30 0 CO (l/min) rest slight exercise Linear PAP increase with CO increase Exercise PAP strongly age-dependent PAP/CO-slope ≈ 1 mmHg/L/min PAP/CO strongly age-dependent CO = cardiac output Kovacs et al. Eur Respir J 2012;39:319-328 Kovacs et al. Eur Respir J 2009;34:888-894 TPR and PVR at TPR and PVR at Exercise Exercise  PVR decrease very mild  TPR decrease mild N=237 subjects from 24 RHC  Age-dependent studies with biphasic • individual values of PAP – CO + PAP ± PAWP Red <24 yr PAWP Green 24-50 yr • Age groups, yrs TPR Blue 51-69 yr – <24 Yellow ≥ 70 yr – 24-50 TPR LVR – 51-69 TPR – >70 PVR PVR • Posture TPR – supine PVR – upright TPR = PVR + LVR PVR=pulmonary vascular resistance Kovacs et al. Eur Respir J 2012;39:319-328 Kovacs et al. Eur Respir J 2012;39:319-328 LVR=left ventricular filling resistance 3

3/9/2019 The Two Components of TPR The Two Components of TPR • TPR = PAP / CO • TPR = PAP / CO • PVR = (PAP-PAWP) / CO = • PVR = (PAP-PAWP) / CO = PAP/CO-PAWP/CO • PVR = TPR – PAWP/CO • PVR = TPR – PAWP/CO   • TPR = PVR + PAWP/CO Vascular component Cardiac component „LV filling resistance“ Kovacs et al. Eur Respir J 2012; 39:319-328 Kovacs et al. Eur Respir J 2012; 39:319-328 Kovacs et al. Eur Respir J 2017; 50:170578 Kovacs et al. Eur Respir J 2017; 50:170578 LV Filling Resistance Change During Exercise is Exercise Hemodynamics: Not So Easy! Strongly Age-Dependent • Previous exercise definition of PH abandoned in Dana Point, 2009. Red <24 yr Green 24-50 yr TPR Blue 51-69 yr Yellow ≥ 70 yr TPR LVR Galie et al. EHJ 2004; 25:2243-2278 TPR PVR PVR TPR = PVR + LVR Galie et al. Guidelines Eur Heart J PVR=pulmonary vascular resistance 2009;30:2493-2537 LVR=left ventricular filling resistance Kovacs et al. Eur Respir J 2012;39:319-328 4

3/9/2019 Why was the exercise definition Can we redefine „exercise PH“? abandoned in 2009? • Complex interaction of age and exercise level on PAP • Complex pathologic mechanisms • Difficulty to define normal values for PAP during exercise • No solid data for transition from „exercise induced PH“ to manifest PH • N= 169 patients with PAP <21 mmHg • No solid data for impact on mortality – N= 49 pulmonary vascular disease Not because exercise PAP was irrelevant!!! – N= 52 left heart disease – N= 68 healthy controls Hervé et al. ERJ (1Sept) 2015;46:728-737 Pressure -Flow Diagram Task Force New Definition ? Max. mPAP >30 mmHg • Provisional definition and max TPR >3 WU of „exercise PH“ – mPAP during exercise >30 mmHg – TPR > 3 WU • Both conditions must be met – at maximal exercise LHD=left heart disease PVD=pulmonary vascular disease Hervé et al. ERJ (1Sept) 2015;46:728-737 Kovacs et al. ERJ 2017; 50:170578 5

3/9/2019 Important Major statements Considerations • Exercise causes mild TPR- and very mild PVR decrease • Essential measurements • PAPm/CO -slope – PAPm+PAWP+CO „simultaneously“ – independent of sex • Supplementary measurements – dependent on age – Right atrial pressure – Weight-effects unknown – Systemic blood gas analysis – Pulmonary blood gas analysis • Posture effects (supine vs. standing) vanish during exercise. • Exercise duration • Treadmill exercise (vs. cycle) poorly investigated – Up to 10 min • Safety – Only after thorough resting investigation – Not in instable patients – Justification in healthy controls difficult Kovacs et al. ERJ 2017; 50:170578 Kovacs et al. ERJ 2017; 50:170578 Causes of Exercise PH Consequences of Exercise PH? • Decisions for aortic and mitral valve intervention! • Vasculopathy Gaine et al. • Unmasking pathologic mechanisms (!) – PVR – Unexplained dyspnea on exertion – Group 1 vs. Group2 vs. Group 3 PH • Left ventricular • Risk stratification? congestion • Monitor treatment effects? – PAWP Source: medscape • Trapped air – Esophageal pressure Source: wikipedia – RAP Kovacs et al. ERJ 2017; 50:170578 6

3/9/2019 Conclusion Effect of Exercise PH on Prognosis??? • Impact of mild PAP elevation on PexNet ERS Sponsored Trial „PexNet“ • Design – Survival ! Study design This is an international, multi-centre, non-interventional registry – Physical capacity ! – International Registry study. Only data of patients with a clinically indicated right heart catheterization and available hemodynamic data both at rest and – PAP/CO slope ! – Clinically indicated RHC during exercise will be included. In the retrospective part, prevalent data provided by the centres will – Peak CO ! at rest and exercise be analysed. In the prospective part, patients undergoing right heart catheterization will be asked that their data may be entered into the • Retrospective databank in a prospective manner. • Association of mild PAP elevation with • Prospective Study objectives – Age We aim to investigate the prognostic relevance of pulmonary • Objectives hemodynamics during exercise as assessed by right heart – Comorbidities catheterization in patients without PH by using a multi-centre – Prognostic relevance approach and to identify independent predictors of adverse events in • Impact of exercise PH ? multivariate analysis. Separate data sets will be analysed for the • Death retrospective and prospective evaluation. Primary end point of the study is mortality / lung transplantation. – Wait for PexNet ! • Other adverse events Main secondary end points are hospitalization and development of PH. Predefined subgroup analyses include patients with systemic sclerosis, patients with coexisting lung disease, patients with PH, patients with left heart disease and patients with chronic thromboembolic disease. Kovacs / Hervé / Olschewski Zero Reference Level Matters Targeting Left Atrium for ZRL Non-standard ZRL is a major confounder ! 5 cm below sternal surface (A) 2/3 thoracic diameter (B) 1/2 thoracic diameter (C) ½ thoracic diameter 10 cm above table (D) Pressure reading (A) = pressure reading (B) if thoracic diameter = 15 cm N=149 patients by thoracic diameter Average thoracic diameter = 25 cm Average difference between A and B = 10 cm H 2 O = 7.8 mmHg Kovacs G, Avian A, Olschewski A, Olschewski H. Zero reference level for RHC. Kovacs et al. ERJ 2013: 42:1586-1594 Eur Respir J 2013 ;42(6):1586-94. 7

3/9/2019 Breath Hold Positive pressure Spontaneously ventilated patient breathing patient control exercise • Measurement at end • Measurement at end expiration??? expiration! Airway pressure COPD exercise Airway pressure t t • Floating average Phlebostatic axis (Winsor&Burch over several breaths! 1945) and suggested reference point Kovacs et al. AJRCCM 2014;190:252-257 8