How biology informs treatment decisions Professor Irene Lang - - PowerPoint PPT Presentation

▶

Aug 24, 2022 304 likes •385 views

How biology informs treatment decisions Professor Irene Lang Professor of Vascular Biology Medical University of Vienna Vienna, Austria Disclaimer Unapproved products or unapproved uses of approved products may be discussed by the faculty;

SLIDE 1

Professor Irene Lang

Professor of Vascular Biology Medical University of Vienna Vienna, Austria

How biology informs treatment decisions

SLIDE 2

Unapproved products or unapproved uses of approved products may be discussed by the faculty; these situations may reflect the approval status in one or more jurisdictions. The presenting faculty have been advised by touchIME to ensure that they disclose any such references made to unlabelled or unapproved use. No endorsement by touchIME of any unapproved products or unapproved uses is either made or implied by mention of these products

r uses in touchIME activities.

touchIME accepts no responsibility for errors or omissions.

Disclaimer

SLIDE 3

ADAMTS13–VMF axis is implicated in underlying CTEPH pathophysiology

Ag, antigen; CTEPH, chronic thromboembolic pulmonary hypertension; PAE, pulmonary endarterectomy; PH, pulmonary hypertension; VMF, von Willebrand factor.

1. Newham M, et al. Eur Respir J 2019:53:1801805; 2. Pazenboeck A, et al. Eur Heart J 2018;39:P1621.

✔Plasma ADAMTS13 antigen levels are markedly decreased in CTEPH, independent of pulmonary hypertension, disease severity or systemic inflammation:1 ▪ ADAMTS13 levels remained low after reversal

f pulmonary hypertension by PAE surgery

▪ A genetic variant near the ADAMTS13 gene was associated with ADAMTS13 protein that accounted for ∼8% of the variation in levels ✔An earlier study did not demonstrate decreased ADAMTS13 activity in CTEPH versus PH2

Healthy control, n=68; CTEPH, n=208

Patients with CTEPH had decreased ADAMTS13 and increased VWF levels compared to healthy controls

ADAMTS13:Ag VMF:Ag

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.0 4.0

Healthy control CTEPH

10 20 30 40 50 60 70 80

Healthy control CTEPH

p⩽0.0001 p⩽0.0001

SLIDE 4

Incidence of CTEPH after acute pulmonary embolism

Percentages show pooled incidence of PE (n=4,047). All comers were defined as unselected consecutive PE patients, survivors as PE patients who survived the first 3 to 6 months after diagnosis, and survivors without comorbidities as survivors without cardiopulmonary, malignant and/or other severe comorbidities. CTEPH, chronic thromboembolic pulmonary hypertension; PE, pulmonary embolism. Klok FA, et al. J Thromb Haem 2018;16:1040–1051.

Survivors without major comorbidities All comers with PE Survivors

f PE

Odds ratio⚡️ ⚡️ recurrent unprovoked

3.17 4.13

0.56% 2.79% 3.22%

SLIDE 5

Microvasculopathy in CTEPH involving pulmonary arterioles, venules and capillaries1,2

CTEPH, chronic thromboembolic pulmonary hypertension; PAH, pulmonary arterial hypertension; PVOD, pulmonary veno-occlusive disease.

1. Dorfmuller P, et al. Eur Respir J 2014;44:1275–1288; 2. Simonneau G, et al. Eur Respir Rev 2017;26:160112.

Distal thrombosis

f pulmonary

artery with partial recanalization Capillary lesion-like hemangiomatosis PAH-like lesions of muscularized arterioles Venular fibrosis and muscularization- like PVOD

Pulmonary artery Pulmonary vein

SLIDE 6

Risk–benefit assessment for surgery

* Not contraindications. DVT, deep vein thrombosis; PA, pulmonary artery; PE, pulmonary embolism; PVR, pulmonary vascular resistance. Kim NH, et al. Eur Respir J 2019;53:1801915.

Higher risk with less predictable long-term outcome* No history of DVT/PE Signs of right heart failure Significant concomitant lung or left heart disease Functional limitation: class IV Inconsistency of imaging modalities No disease appreciable in lower lobes PVR<1200 dyn.s.cm-5 out of proportion to site and number of

bstructions on imaging, higher PA diastolic pressure

Lower risk with predictable good long-term outcome History of DVT/PE No signs of right heart failure No comorbidities Functional limitation: class II or III Clear disease concordant on all images Bilateral lower lobe disease PVR<1000 dyn.s.cm-5 in proportion to site and number of

bstructions on imaging, higher PA pulse pressure

SLIDE 7

NO-sGC-cGMP pathway in PH: A new therapeutic target

NO-sGC-cGMP, nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP); NOS, NO synthase; PDE-5, phosphodiesterase-5; PH, pulmonary hypertension. Kim NH. Eur Respir Rev 2010;19:69–71.

L-arginine NOS NO sGC cGMP GMP Vasorelaxation

PDE-5

X

L-arginine L-citrulline

Stimulation of sGC Inhibition of PDE-5