proteomics: addressing gaps of care in heart failure...ongoing challenges in hf •why did this...

Proteomics:

Addressing Gaps of Care

in Heart Failure

Peter Liu, M.D.

University of Ottawa Heart Institute

University of Toronto

Cda Invented BasketB

• The game Basketball became

a demonstration sport during

the 1913 Olympic Games

• Naismith also invented the

first football helmet

Pre-Emptive HF Care 2030• While playing golf on Amelia Island, iPhone 20

Alert for you: Message from Ms HF, fatigue and personal health monitor alarm (iWatch 9)

• Hx Alert: +ve FH of CM: BAG3/Titin risk

• You recommend her to apply personal health Dx patch #15 (on sale Amazon Prime Day)

• Remote activation of Dx panel – BNP, hsTn, GDF-15 & IGFBP7 trending up; AI diagnosis of HF subtype H21, recommend mitigation: M12

• Contact pt by VR, recommend M12 combo, reminder regarding exercise and HH diet.

5

Ongoing Challenges in HF

• Why did this particular patient end up

with heart failure at this time?

• What exactly is wrong with his/her

heart/vessels to cause this?

• Is this situation dangerous?

• What are the best treatments?

• Could we ID a new Rx for the pt?

• Is this situation reversible?

Proteomic Applications in Heart Failure

Gel -Free LC-MS

Patient Samples

from (Nested) Case

Control Cohorts

±

Aptamer DNA Arrays

±

± Relevant Murine Models

Ab Prox Extension Assay

Urine

Plasma Tissue(if available)

Available Proteomic

Technologies

Bayes-Genis A, Liu, Januzzi. J Am Coll Cardiol 2019 (in press)

Proteomics in Heart Failure

•Approaches in protein analysis

• Insight into HF processes

•Biomarkers for Dx/Px

•Disease classification

•Therapeutic development

Tools Arising

from the

Expressed

Genome –

“Omics”

Musunuru, Ingelsson, Liu, et al. Circulation

Genomics Prec Med 2017; 10:e00037

NPPB NPPA ANG

Mimecan GDF15 TIMP1 TNFXXXCHI3L1

Proteins significantly increased in HEpEF patient plasma

IGFBP7

CXXXXX CXXX AXXX CXXX2EGFR Transferrin

Proteins significantly decreased in HEpEF patient plasma

Examples of established biomarkers for HFrEF

Group 1: HEpEF; 2: DCM; 3, ICM,; 4: Healthy control

Aptamer Proteomics: Biomarkers for HFpEF (vs HFrEF)

Neural Network Deep Learning on RHF Markers

Prostaglandin G/H

synthase 2 (P35354)

Ephrin-B3 (Q15768)

Matrilin-3 (O15232)

Asialoglycoprotein

receptor 1 (P07306)

Fibroblast growth

factor 12 (P61328)

0: Healthy

1: RHF

miR & Protein Patterns in HF

14Isserlin R, Gramolini A, Emili A, et al., Mol Biosyst 2015; 11:239-51

Inflammatory Markers & Prognosis in HFpEF

Hage C, Lund LH, et al., Circulation Genomics Prec Med 2017;10:e001633

Predictors of Mortality in Multinational

Observational Cohort on Acute Heart Failure (MOCA) Study

Mebazza A, et al. Int J Cardiol 2013; 168(3):2186-94

Proteomics of Mitochondrial

Proteins in HF

Aubert, Kelly D, et al. Circulation 2016

Mechanisms of SGLT2i in HF

Wanner, Marx. Diabetologica 2018; 61:2134-9

Biomarkers Resembling Art:

Is It Real,or Merely

a Passing Fancy?

Salvatore

Mundi

Biomarkers as Clues to HF

26Chow C, et al., Circulation 2017; 135: e1054-e1091

Protein Markers Predicting HF in Elderly

Stenemo, Arnlov, et al., European J Heart Fail 2018; 20:55-62


Gel -Free LC-MS

Network A(e.g. Immunity, Senescence)

Patient Samples

from (Nested) Case

Control Cohorts

±

Aptamer DNA Arrays

Network B(e.g. Metabolism)

Network C(e.g. Matrix Remodeling)

± Machine Learning/AI

±



Urine


Available Proteomic

Technologies

Biomarker Validation

Bayes-Genis A, Liu, Januzzi.

JACC 2019 (in press)

Heterogeneity of HFpEF by Clinical Presentation

Senni et al, Eur Heart J 2014

ComorbiditiesMechanisms

Reddy et al, Circulation 2018

MS Proteomic HF Markers

Chugh, Liu, Gramolini, Proteomics 2013; 13:2324-34; Epub prior to print

Diastolic Func’n by IGFBP7 Tertiles

Gandi, Liu, Januzzi, et al., Am J Cardiol 2014, 114:1543-1549

IGFBP7 Prognostic in I-PRESERVE

Ghandi, O’Connor, Anand, et al., J Card Failure 2016

For every 70 ng/ml

increase in

IGFBP7, the

mortality doubles

HFpEF vs Control using IGFBP7

From Imprecise to PrecMed

Bayes-Genis, et al., Eur Heart J 2018; 39:2793-8

IGFBP7 & Stress

p<0.001p<0.0

5p<0.001

NS Igfbp7-/-

Igfbp7+/+

WGA DAPI WGA DAPI

Igfbp7-/-Igfbp7+/+

sham

TAC

p<0.001

NS

dc

ba

p<0.05

NS

IGFBP7 & Fibrosis

p<0.05

Igfbp7-/-Igfbp7+/+

sh

am

TA

C

a

Gapdh 35

Igfbp7+/+ Igfbp7-/-

sham shamTAC TAC

CTGF 35

p<0.05

b

Utility of Biomarkers for Precision

Medicine in Heart Failure

44

EtiologyRemo-deling

TreatmentOptions

Response

Symptoms / Prognosis

EtiologyRemo-deling

TreatmentOptions

Response

IGFBP7 in PARAMOUNT

Januzzi J, Solomon S, et al, Circ Heart Failure 2018; 11:005133

Adrenomedullin in HF

Voors, Butler J, et al. Eur J Hrt Fail 2019


Gel -Free LC-MSResponse

to Rx

RxTrial

Network A(e.g. Immunity, Senescence)

Patient Samples

from (Nested) Case

Control Cohorts

±

Aptamer DNA Arrays

Network B(e.g. Metabolism)

Network C(e.g. Matrix Remodeling)

± Machine Learning/AI

±



Urine


Available Proteomic

Technologies

Biomarker ValidationSystem Biol Integration Precision Medicine

Bayes-Genis A, Liu, Januzzi.

JACC 2019 (in press)

Precision Mapping of Fibrosis Markers

49

CITP/PIIINP/Gal-3

Metabolic Targets in Fibrosis

Xiao, Liu, et al. Nature Review Drug Discovery 2019 (in press)

Partnership to Realize PrecMed

51

HFPatient

Bio-MarkerTeam

Rx Develop

Team

FDA/EMAPayers

Providers/

Omics/AI

A Takotsubo moment…..

54

Conclusions• Systems biology approaches permit

discovery of novel pathophysiological relevant biomarkers in heart failure

• For PrecMed, biomarkers should inform disease process and ID HF subtypes

• Ideal biomarker also identify therapeutic choices and potential response to Rx

• Collaboration amongst translational and clinical researchers, industry and regulators will be needed to move the field forward

proteomics: addressing gaps of care in heart failure...ongoing challenges in hf •why did this...

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