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

▶
conflict of interest
SMART_READER_LITE
LIVE PREVIEW

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

Jan 08, 2023 117 likes •204 views

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,

slide-1
SLIDE 1

3/9/2019 1

Borderline and Exercise Induced PH

Horst Olschewski Universitätsklinik für Innere Medizin Klinische Abteilung für Lungenkrankheiten Graz, Österreich

Mildly elevated PAP and Exercise PH Conflict Of Interest

Grants/Boards: Actelion, Bayer, Bellerophon, Boehringer, Inventiva, Roche, Ludwig Boltzmann Society Speaker: Actelion, Boehringer, Chiesi, Menarini, Mondial, MSD, Novartis Consultancy: Actelion, Astra Zeneca, Bayer, Boehringer, Chiesi, GSK, Menarini, Novartis

Pulmonary Arterial Pressure At Rest

5 10 15 20 s u p i n e u p r i g h t m a l e s f e m a l e s i n E u r

  • p

e i n U S A < 3 y r 3

  • 5

y r > 5 y r mean PAP (mmHg)

Kovacs et al. Eur Respir J 2009;34:888-894

PAP = 14.0 ± 3.3 mmHg ULN = 20.6 mmHg

Systematic literature research N=1121 healthy subjects RHC at rest and exercise

ULN=upper limit of normal PAP 21-24 = „borderline PAP“

Borderline PAP

  • N=141 patients with PAP <25 mmHg

– 31 patients with PAP 21-24 mmHg („borderline PAP“) – 110 patients with PAP < 21 mmHg („normal“)

  • Borderline PAP is associated with

– Increased age and comorbidities – Increased PAP/CO slope – Increased mortality

Kovacs et al. CHEST 2014; 146: 1486-1493

slide-2
SLIDE 2

3/9/2019 2

Reduced Survival in Borderline PAP

Kovacs et al. CHEST 2014; 146: 1486-1493

borderline PAP normal PAP

PAP 21-24 mmHg vs. PAP <21 mmHg: Mortality rate 19 % vs. 4 % /4.4 yr

„Borderline PH“ associated with mortality

  • N= 21.727 patients

– 97% male (VA) – Median age 65 yr – Median PAP 26 mmHg

Maron et al. Circulation 2016; 133:1240-1248

mPAP ≥ 19 mmHg associated with increased mortality

  • Retrospective + prospective evaluation

– N=392+153 patients – Follow-up 46 months [22-77]

  • Mortality

– according to preset thresholds based on PH definition and normal values (HR corrected for age+comorbidities)

– Lower normal (up to norm + SD) HR=1 – Upper normal (norm +1 SD to norm +2SD) HR=2.0 [0.9-4.5] – Borderline (21-24 mmHg) HR=2.4 [1.1-5.0] – PH (≥25 mmHg) HR=5.1 [2.8-9.1] Douschan et al. AJRCCM 2018;197:509-516 HR = hazard ratio

  • PH: previously „≥ 25mmHg“ now

„> 20mmHg“

  • i.e. from 25 down to 21
  • Precapillary PH

– PAWP ≤ 15mmHg – PVR ≥ 3 WU (240 dyn s cm-5)

  • Isolated postcapillary PH

– PAWP >15 mmHg – PVR < 3 WU (240 dyn s cm-5)

  • Combined pre+postcapillary PH

– PAWP >15 mmHg – PVR ≥ 3 WU (240 dyn s cm-5) Simonneau et al. ERJ 2019; 53: 1801913

6th WSPH Nice 2018

Hemodynamic Definition

slide-3
SLIDE 3

3/9/2019 3

Dependency of PAP from CO

Kovacs et al. Eur Respir J 2012;39:319-328

CO = cardiac output

5 10 15 20 25 30 35 5 10 15 20 25 30 CO (l/min) mean PAP (mmHg)

Pulmonary Arterial Pressure At Exercise

10 20 30 40 rest slight exercise mean PAP (mmHg)

Kovacs et al. Eur Respir J 2009;34:888-894

Linear PAP increase with CO increase Exercise PAP strongly age-dependent

>50 yr >30-50 yr <30 yr

PAP/CO-slope ≈ 1 mmHg/L/min PAP/CO strongly age-dependent

Kovacs et al. Eur Respir J 2012;39:319-328 PAP PAWP TPR PVR

TPR and PVR at Exercise

N=237 subjects from 24 RHC studies with

  • individual values of

– CO + PAP ± PAWP

  • Age groups, yrs

– <24 – 24-50 – 51-69 – >70

  • Posture

– supine – upright

PVR

Red <24 yr Green 24-50 yr Blue 51-69 yr Yellow ≥ 70 yr

TPR

TPR = PVR + LVR PVR=pulmonary vascular resistance LVR=left ventricular filling resistance Kovacs et al. Eur Respir J 2012;39:319-328

TPR PVR LVR TPR

  • PVR decrease very mild
  • TPR decrease mild
  • Age-dependent

biphasic

TPR and PVR at Exercise

slide-4
SLIDE 4

3/9/2019 4

The Two Components of TPR

  • TPR = PAP / CO
  • PVR = (PAP-PAWP) / CO =
  • PVR = TPR – PAWP/CO

Kovacs et al. Eur Respir J 2017; 50:170578 Kovacs et al. Eur Respir J 2012; 39:319-328

The Two Components of TPR

  • TPR = PAP / CO
  • PVR = (PAP-PAWP) / CO = PAP/CO-PAWP/CO
  • PVR = TPR – PAWP/CO
  • TPR = PVR + PAWP/CO

Vascular component Cardiac component „LV filling resistance“

Kovacs et al. Eur Respir J 2017; 50:170578 Kovacs et al. Eur Respir J 2012; 39:319-328

PVR

Red <24 yr Green 24-50 yr Blue 51-69 yr Yellow ≥ 70 yr

TPR

TPR = PVR + LVR PVR=pulmonary vascular resistance LVR=left ventricular filling resistance Kovacs et al. Eur Respir J 2012;39:319-328

TPR PVR LVR TPR

LV Filling Resistance Change During Exercise is Strongly Age-Dependent

Exercise Hemodynamics: Not So Easy!

  • Previous exercise definition
  • f PH abandoned in Dana

Point, 2009.

Galie et al. Guidelines Eur Heart J 2009;30:2493-2537

Galie et al. EHJ 2004; 25:2243-2278

slide-5
SLIDE 5

3/9/2019 5

Why was the exercise definition 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

  • No solid data for impact on mortality

Not because exercise PAP was irrelevant!!!

Can we redefine „exercise PH“?

  • N= 169 patients with PAP <21 mmHg

– N= 49 pulmonary vascular disease – N= 52 left heart disease – N= 68 healthy controls

Hervé et al. ERJ (1Sept) 2015;46:728-737

Pressure -Flow Diagram

New Definition ?

  • Max. mPAP >30 mmHg

and max TPR >3 WU

Hervé et al. ERJ (1Sept) 2015;46:728-737

LHD=left heart disease PVD=pulmonary vascular disease

Task Force

  • Provisional definition
  • f „exercise PH“

– mPAP during exercise >30 mmHg – TPR > 3 WU

  • Both conditions must

be met

– at maximal exercise

Kovacs et al. ERJ 2017; 50:170578

slide-6
SLIDE 6

3/9/2019 6

Important Considerations

  • Essential measurements

– PAPm+PAWP+CO „simultaneously“

  • Supplementary measurements

– Right atrial pressure – Systemic blood gas analysis – Pulmonary blood gas analysis

  • Exercise duration

– 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

Major statements

  • Exercise causes mild TPR- and very mild PVR decrease
  • PAPm/CO -slope

– independent of sex – dependent on age – Weight-effects unknown

  • Posture effects (supine vs. standing) vanish during exercise.
  • Treadmill exercise (vs. cycle) poorly investigated

Kovacs et al. ERJ 2017; 50:170578

Causes of Exercise PH

  • Vasculopathy

– PVR

  • Left ventricular

congestion

– PAWP

  • Trapped air

– Esophageal pressure – RAP

Source: medscape Source: wikipedia Gaine et al.

Consequences of Exercise PH?

  • Decisions for aortic and mitral valve intervention!
  • Unmasking pathologic mechanisms (!)

– Unexplained dyspnea on exertion – Group 1 vs. Group2 vs. Group 3 PH

  • Risk stratification?
  • Monitor treatment effects?

Kovacs et al. ERJ 2017; 50:170578

slide-7
SLIDE 7

3/9/2019 7

Effect of Exercise PH on Prognosis???

PexNet

  • Design

– International Registry – Clinically indicated RHC at rest and exercise

  • Retrospective
  • Prospective
  • Objectives

– Prognostic relevance

  • Death
  • Other adverse events

Study design This is an international, multi-centre, non-interventional registry

  • study. Only data of patients with a clinically indicated right heart

catheterization and available hemodynamic data both at rest and during exercise will be included. In the retrospective part, prevalent data provided by the centres will be analysed. In the prospective part, patients undergoing right heart catheterization will be asked that their data may be entered into the databank in a prospective manner. Study objectives We aim to investigate the prognostic relevance of pulmonary hemodynamics during exercise as assessed by right heart catheterization in patients without PH by using a multi-centre approach and to identify independent predictors of adverse events in multivariate analysis. Separate data sets will be analysed for the retrospective and prospective evaluation. Primary end point of the study is mortality / lung transplantation. 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.

ERS Sponsored Trial „PexNet“

Kovacs / Hervé / Olschewski

Conclusion

  • Impact of mild PAP elevation on

– Survival ! – Physical capacity ! – PAP/CO slope ! – Peak CO !

  • Association of mild PAP elevation with

– Age – Comorbidities

  • Impact of exercise PH ?

– Wait for PexNet !

2/3 thoracic diameter (B) 1/2 thoracic diameter (C) 10 cm above table (D) 5 cm below sternal surface (A)

Non-standard ZRL is a major confounder !

Zero Reference Level Matters

Pressure reading (A) = pressure reading (B) if thoracic diameter = 15 cm Average thoracic diameter = 25 cm Average difference between A and B = 10 cm H2O = 7.8 mmHg Kovacs G, Avian A, Olschewski A, Olschewski H. Zero reference level for RHC. Eur Respir J 2013 ;42(6):1586-94.

Targeting Left Atrium for ZRL

Kovacs et al. ERJ 2013: 42:1586-1594

N=149 patients by thoracic diameter

½ thoracic diameter

slide-8
SLIDE 8

3/9/2019 8

Kovacs et al. AJRCCM 2014;190:252-257

control COPD Phlebostatic axis (Winsor&Burch 1945) and suggested reference point exercise exercise

Breath Hold

Positive pressure ventilated patient

  • Measurement at end

expiration! Spontaneously breathing patient

  • Measurement at end

expiration???

  • Floating average
  • ver several breaths!

t Airway pressure t Airway pressure