Advances in Heart Failure

Patient Management,
ST2 Testing
Outline

Basic Concepts in ST2

Prognosis

Monitoring and Treatment Selection

Case Studies

Presage ST2 Assay Kit

2
Heart Failure
HF Revolving Door

4
Potential Clinical Uses of Biomarkers

ST2
CREATINE
TROPONIN
KINASE

CK-MB NP MARKERS

MYOGLOBIN

DIAGNOSIS PROGNOSIS/MANAGEMENT

5
 What is ST2?
ST2 (growth STimulation expressed gene 2) is a member of the Interleukin-1
receptor family, and is formally known as interleukin 1 receptor like 1 (IL1RL-1).
IL-33 is its ligand.

Was first reported in 1989, but its function was not well elucidated.

In 2002, Richard Lee at Harvard B&W reported ST2 expression in response to

myocardial stress and injury.

ST2 is expressed by cardiac tissue.

Subsequently ST2 was shown to be actively involved in the fibrotic response to
illness or injury.
Exists in two main isoforms through alternative splicing and processing.
ST2L is a membrane-bound isoform with 3 extracellular IgG domains, a single
transmembrane domain, and an intracellular domain.
ST2 is a soluble, circulating isoform, lacks the transmembrane and intracellular
domains.
 ST2: A DECOY RECEPTOR
Pro-IL-33
Fibroblast
Caspase-1
Myocyte

IRAK

IL-33 ST2L MyD88

ERK NFkB

ST2
Anti remodeling
Anti hypertrophy
Anti fibrosis
CARDIOPROTECTION
Kakkar et al. Nat Rev Drug Discov 2008
 2013 ACCF/AHA Guideline for the
Management of Heart Failure

As a biomarker of myocardial fibrosis, soluble ST2 is not only predictive of

hospitalization and death in patients with HF but also additive to natriuretic
peptide levels in their prognostic value. Strategies that combine multiple
biomarkers may ultimately prove beneficial in guiding HF therapy in the future.
 Chinese Guideline for Heart Failure
Diagnosis and Treatment 2014

ST2
(IIa, B)

ST2
(IIb, A)
 Easy to Use:
Single Cutpoint

>
ng/mL

= RISK
 ST2 is Associated with Symptom Severity
NYHA Class NYHA Class
200.0 200.0

180.0 180.0

160.0 160.0

ST2 Concentration (ng/ml)

ST2 Concentration (ng/ml)

140.0 140.0
P<0.0001 P<0.0001
120.0 120.0

100.0 100.0

80.0 80.0

60.0 60.0

40.0 40.0

20.0 20.0

- -
NYHA Class 1 NYHA Class 2 NYHA Class 3 NYHA Class 4 NYHA Class I NYHA Class II NYHA Class III NYHA Class IV

Acute HF (PRIDE) Chronic HF (PHFS)

ST2 Not Correlated with Renal Function

In a cohort of 879 heart failure patients ST2 did not show any correlation with
renal function whereas NT-proBNP concentrations increased significantly with
decreasing renal function.

Bayes-Genis et al. 2013 JCF

Recommended HF Management
Mode

BNP/NT-proBNP
+
ST2
 When to Detect ST2
1. Inpatient setting
Destablised HF (Acutely Decompensated HF)
If one considers a 7 day average LOS (length of stay in hospital).
The diagnosis :
may include clinical judgement (or echo/x-ray/ NT-proBNP).
ST2 baseline value:
ST2 should be assessed within 24hrs of admission to establish severity and
risk
Hospital stay:
ST2 may be evaluated during hospital stay (day 3 or 4), to evaluate and guide
the therapy
Hospital discharge: certainly 24hrs before discharge

Post-MI
ST2 should be measured in the FIRST 24hrs following MI. A follow-up ST2
may be at day 5 or 10. When discharged, above should apply dependent on risk
profile.
Algorithm for using ST2 in acute myocardial infarction patients
STEMI or moderate-high risk NSTEMI
LEVF<40%

Optimize beta blocker and ACEI/ARB

Measure ST2

< 35 ng/mL 35 ng/mL

Continue current K<5.0 meq/L

management
No Yes

No Serum creatinine
Defer additional
<2.5 mg/dL (menor
therapy
<2.0 mg/dL (women?
Yes
Provide close clinical Start spironoiactone
follow-up 25 mg daily

Laboratory
monitoring and dose
Daniels LB.2014) ST2: how to really do it right. In: Heart Failure: The Experts
Approach, Chapter 34, Alan S Maisel, Gerasimos S Filippatos. pp 283-288. titration as indicated
2. Ambulatory (outpatient) setting
Chronic HF
Dependent on risk of patient, it may be appropriate (for high risk HF) to re-
measure ST2 after 1 week. Dependent on concentration of ST2 (remember target
is below 35ng/ml) will determine the frequency of ST2 testing:
High risk (significantly above 35ng/ml) 2 weeks 1 month intervals
(Intermediated moderately above 35ng/ml) 1 month 3 month intervals)
Low risk (below 35ng/ml) 3 6 month intervals
Algorithm for using ST2 in chronic heart failure patients
Chronic heart failure with severe symptoms or
recent decompensation

Optimize beta-blocker, ACEI/ARB, loop diurectic

therapies

Symptomatic or recent HF decompensation?

Measure ST2

< 35 ng/mL 35 ng/mL

Continue current K<5.0 meq/L

management
No Yes

Repeat ST2 No Serum creatinine

Defer additional
in 2 weeks <2.5 mg/dL (menor
therapy
<2.0 mg/dL (women?
Yes
ST2 reduced 25% ST2reduced25% Provide close clinical Start spironoiactone
(2 week/baseline) (2 week/baseline) follow-up 25 mg daily

Continue current Laboratory

management monitoring and dose
Daniels LB.2014) ST2: how to really do it right. In: Heart Failure: The Experts
Approach, Chapter 34, Alan S Maisel, Gerasimos S Filippatos. pp 283-288. titration as indicated
Prognosis
Mortality Risk Increases With ST2 Levels
One-year mortality exceeded 50% in the highest decile

ST2 Decile
Rehman SU, Mueller T, Januzzi JL et al. J Am Coll Cardiol. 2008;52:1458-65.
 In Chronic HF Risk is Much Higher
if ST2 >35 ng/mL

Adapted from Ky et al.(2011) Cir Heart Fail, 4:180-187

Additive Value of ST2 to NT-proBNP:
Acute HF
0.8 Both sST2 and NT-proBNP elevated (n=276)
Only sST2 elevated (n=95)
Only NT-proBNP elevated (n=54)
Neither elevated (n=168)
Cumulative Hazard

Reclassification
0.6

P < 0.001
0.4

0.2

0.0

0 300 600 900 1200 1500

Days from Enrollment

Patient would have been classified as moderate risk with only

NT-proBNP, but is considered high risk with the addition of ST2.

Rehman SR, van Kimmenade RR, Januzzi JL. Circulation. 2008;118:S_871.

Monitoring and Treatment
Selection
Multivariate Analysis of ST2, BNP, and cTnT:
Serial ST2 Testing Dominates Multimarker Model
2.0
1.8 P < 0.001
1.6
P = 0.001
1.4 P = 0.02
Hazard Ratio

1.2
1.0
0.8
0.6
0.4
0.2
0.0
ST2 ST2 + BNP ST2 + BNP + cTnT

Saenger AK, Miller WL, Lueke AJ et al. Circulation. 2012;126:A19365.

ST2 Trends as a function of Mortality
90-day mortality 1-yr mortality

N=35 N=69

N=115
N=68
 ST2 Levels Predict Response to
Treatment: BB

2 p=0.62
p=0.1
3
Cumulative survival

1 BB treated ST2 responder Risk is not absolute!

2 BB treated ST2 non-responder It can be attenuated!!
3 untreated ST2 responder
4 untreated ST2 non-responder

Days
Breidthardt, et al. 2013 JCF
ST2 Provides Actionable Information

Chronic heart failure patient

Substantial fall of ST2 following medications
Slight upturn of ST2 value after stopping aldo blocker
Adapted from Professor James L. Januzzi, Jr, Massachusetts General Hospital, USA
ST2 Provides Actionable Information

14 times of measurements in one-year setting

Concentration drops to normal level (<35ng/mL) after treatments and exercise
ST2 value nearly doubled after a salty meal
ST2 provided high-risk finding from patient with only mild symptoms
Adapted from Professor James L. Januzzi, Jr, Massachusetts General Hospital, USA
CV Events by Baseline ST2 and
BB Dose

Gaggin et al. 2013 Circ HF

Primary Results
Prediction Score
Case Studies
 Case: Stage B NYHA Class I HF

85 year-old male with non-ischemic cardiomyopathy

secondary to hypertension
LVEF is 35% with mild mitral regurgitation (MR)
History of paroxysmal AF, but currently in sinus rhythm
At every visit, his NT-proBNP has been < 1000 pg/mL
(the "target").

Adapted from Professor Antoni Genis-Bayes, Hospital Universitari Germans Trias i Pujol, Spain
 Case: Stage B NYHA Class I HF
Biomarker Levels and Therapy in Subsequent Visits

ST2
NT-proBNP

Adapted from Professor Antoni Genis-Bayes, Hospital Universitari Germans Trias i Pujol, Spain
 Patient K.E.
35

30 31 Coreg & Eplerenone

ST2 Concentration Levels (ng/mL)

Started

25

20
19
ST2
15

10

Discharge No Re-admission
0 Clinic
8-Jan-15 24-Mar-15

Adapted from Professor Alan Maisel, UCSD, USA

 250
Patient H.V.

Metoprolol 100
ST2 Concentration Levels (ng/mL)

BID
200 200
Hydralazine 10
TID

150

ST2
100 105

50

No Re-admission
Discharge Clinic
0
14-Dec-14 15-Mar-15

Adapted from Professor Alan Maisel, UCSD, USA

 Patient J.G.
180 1000

160 164 900

BNP Concentration Levels (pg/mL)

ST2 Concentration Levels (ng/mL)

140 800
700
120
600
100 550
500 ST2
80 79 ST2 decreased at 78 BNP
both discharges 400
60 350
54 but still very high. 295 300
40 200
20 110 100
0 Admission Discharge Re-admission Discharge 0
28-Mar-15 30-Mar-15 10-Apr-15 13-Apr-15

Adapted from Professor Alan Maisel, UCSD, USA

Presage ST2 Assay Kit
 Origin: USA

Kit: 96-well ELISA kit

FDA cleared and CE marked

41
Who is Using the Presage ST2 Assay?

More
 Marketing in Asia-Pacific
Area Institution
Beijing Fuwai Hospital
Shanghai Zhongshan Hospital
China
Wuhan Asia Heart Hospital

Hong Kong Queen Elizabeth Hospital

Macau Kiang Wu Hospital

National Taiwai University Hospital

Chang Gung Hospital system
Taiwan
Far Eastern Hospital system
Taipei Veterans Hospital
 ST2
Is NOT:
a general inflammation marker
a stretch marker
Is
a marker of fibrosis and worsening HF
prognostic of 30-day rehospitalization
NOT adversely impacted by impaired renal
function or elevated BMI
 ST2 Clinical Applications
Best HF prognostic marker
ST2 Strength Not affected by renal, age, body fat and many
other confounders
Easy to use with single cut point

ST2 Clinical Risk stratification

Provides powerful clinical guidance
Implication An independent prognostic indicator

Early diagnosis (kh hu)

When to Test ST2 A reference before therapy (kh hu)
Monitored during treatment or after treatment

ST2 Suitable Asymptomatic population

Potential HF high-risk population
Population HF confirmed patients