What’s new with cardiac

biomarkers?
James L. Januzzi Jr, MD, FACC FESC
Hutter Family Professor of Medicine, Harvard Medical School
Physician, Cardiology Division, Massachusetts General Hospital
Senior Cardiometabolic Faculty, Baim Institute for Clinical Research
JJanuzzi@partners.org @JJheart_doc

Harvard Medical School

Disclosures

• I disclose the following relationships with industry that are

relevant to my talk:
• Grants: Roche Diagnostics, Prevencio, Novartis, Abbott, Cleveland
Heart Labs
• Consulting: Roche Diagnostics, Novartis, Janssen
• Endpoint/DSMB committees: Abbott, AbbVie, Amgen, Bayer,
Boehringer-Ingelheim, Janssen, Pfizer, Takeda
Topics
•What’s new with:

→Troponin

→Natriuretic peptides
Two-compartment troponin biology

MYOCARDIAL INJURY
Contractile
apparatus
Cytosolic troponin

Responsible for
Responsible for “delayed/persistent”
“early” troponin troponin release
release
 Diagnosis of myocardial infarction

Biomarker indicators of MI
• Troponin is preferred biomarker for
dx of MI

• cTnT or cTnI > 99th %ile on any

determination

• CK-MB > 99th %ile on two successive

measurements or > 2X ULN on any
sample
The Universal Definition
• Type I: spontaneous
• Type II: “demand”
• Type III: associated with SCD
• Type IV
• A: peri-PCI
• B: stent thrombosis
• C: associated with restenosis

• Type V: post-CABG
 High sensitivity troponin assays

•Assays for that have higher

precision (i.e. <10% co-
efficient of variation) at the
99th percentile for a normal
patient population.
 Population measurements of hsTnT
300
Blood donors (n=1251)
Apparently healthy individuals (n=500)
250
Depending on the assay,
up to 75% or more of
Frequency abs.

200 99th percentile= 14 pg/mL Old URL = 0.03 ng/mL

(imprecision 10%) (imprecision 10%) ‘normals’ will have
150 measurable Tn!
100
The term ‘troponin
50 positive’ will become
less useful!
0
0 2 4 6 8 10 12 14 16 18 20 22 50
TnT [pg/mL]
 Higher hsTn concentrations in those without MI
• Age
• Male sex
• Black race
• Kidney function—presence and severity
• Diabetes mellitus—presence and severity
• Hypertension—presence and severity
• Prior CV disease—presence and severity

Irfan et al, Am J Med, 2012; Rubin, et al, Clin Biochem 2016

 Higher hsTn concentrations in those without MI

• Age • CAD
• Male sex – With or without prior MI
• Heart muscle disease
• Black race – LVH
• Kidney function—presence and severity – HF
– HCM
• Diabetes mellitus—presence and severity
• Valve disease
• Hypertension—presence and severity • AF
• Prior CV disease—presence and severity • Pulmonary pressure

Irfan et al, Am J Med, 2012; Rubin, et al, Clin Biochem 2016

hs-Troponin in practice

• High sensitivity assays will bring two things to your

practice:

→Detection of more patients with myocardial

injury/necrosis

→Faster recognition of acute myocardial injury/necrosis

Speed to diagnosis in acute MI
TRAPID-AMI
Approaches to hs-cTn measurement
•Baseline only

•Baseline, 3 hour

•Baseline, 1 hour

•Each, above, but with a clinical ADP

 ED algorithm, MGH
Patient arrives with chest pain
or anginal equivalent1

Order troponin
at presentation
and 1hr later
TROPONIN

ALL troponins <10 ng/L (female) or

Neither Rule in/Rule out
ANY troponin 52 ng/L OR <15 ng/L (male) with Δ <3 ng/L if
Order 3hr troponin, if any criteria for Rule in
Δ > 5 ng/L presenting >3hr after
Zone met, follow recommendation
symptom onset

Observation Rule Out

Rule In Zone Observation zone
Zone Zone
RISK SCORE

HEART 0-6: Low & HEART 7-10: High HEART 0-6: Low & HEART 7-10: High HEART 0-6: Low &
HEART 7-10: High
Intermediate probability Intermediate probability Intermediate
probability probability probability
probability

ED Observation or
Dispo

Admit to Cardiology Admit to Medicine Discharge Home

further evaluation
More refined! Faster! What could possibly go wrong?
 Ischemia and necrosis: conventional Tn assay
Christ M, AJM 2010, 123:1134

Non-coronary
cardiac necrosis

Ischemia Necrosis

Unstable Angina
AMI
 Ischemia and necrosis: hs-cTn assay
Christ M, AJM 2010, 123:1134

Increase 20-50% Non-coronary

cardiac necrosis

Ischemia
Necrosis

Unstable Angina Increase >200%

AMI
A predictable U.S. response to the advent of hs-cTn

• “The U.S. is different

than Europe!”
• “Everyone will need a
cardiology consult”
• “We’re going to cath
everyone!”
• “Outcomes will be
worsened”
 Troponin testing during ED visits: MGB

• Chest pain patients received

net fewer stress tests,
cardiac catheterizations,
cardiology evaluations,
hospital admissions

Ganguli I, et al, J Am Coll Cardiol, 2021

Dealing with the change to hs-troponin

• Be prepared for the change in units (1000x higher!)

• Accept that you will detect more abnormal values—they are real!
- Understand quantitative troponin concentrations
- Use serial changes
- Know the diff dx of an elevated troponin, including a rising and/or falling value
- Understand troponin is a support to clinical judgment
Sorting out MI from injury

An MI requires injury (e.g. troponin rise

and/or fall, but injury may occur for many
reasons besides MI.

Therefore, you need to have injury plus at

least one of the supporting features:

• Symptoms
• Signs
• Imaging evidence
• Autopsy evidence
The golden rules of troponin testing

• Pre-test probability rules the validity of a post-test result

→Stated another way…don’t test someone with zero likelihood for an ACS

• Troponin is only one component to the diagnosis of acute MI

→With hs-cTn assays, injury is more common than MI

• Clinical judgment is the most important part of how these tests

should be deployed
Differential dx of a rising and/or falling hs-troponin

“Troponin release identifies the presence of myocardial injury/necrosis, but not the mechanism”

• Type I MI • Pulmonary embolism • Chemotherapy

• Type II MI • Critical illness • Stimulant abuse
• Type IV MI • Acute renal failure • COVID19
• Type V MI • Trauma
• Acute heart failure • Transplant rejection • And many more…
• HTN emergency • Aortic dissection
• AF with RVR • Cardioversion
• Apical ballooning • RF ablation
• Myocarditis • Myocardial abscess
• Pericarditis • Envenomation
The differential diagnosis of an abnormal hsTn
Four keys to using NPs intelligently
• Understand why they rise and fall

• Know how to interpret them (even if they don’t seem

to make sense!)

• Know when and why to use them

• Know their expanding potential

 Using natriuretic
peptides clinically
1. Know why they rise and fall
Cardiac Correlates for NP Values

• Left ventricle • Valves

• Systolic function • AS, AI
• Diastolic function • MR, MS
• Chamber size • TR, TS
• Wall thickness
• Filling pressures
• Right ventricle
• Pulmonary
• Systolic function • Left ventricle, left atrial
• Chamber size
• Atria • Coronary ischemia

• Size • Heart rhythm

• Aortic capacitance
Clinical correlates of elevated NPs
• Heart failure
• ACS
• Heart muscle disease
• Pericardial disease
• Valvular heart disease
• Atrial fibrillation
• Pulmonary hypertension
• Myocarditis
• Cardiac surgery
• Congenital heart disease
• Cardioversion
• Advancing age
• Anemia
• Pulmonary embolism
• Sleep apnea
• Critical illness
• Sepsis
• Burns
• Toxic-metabolic insults
• Renal failure
Clinical correlates of elevated NPs
• Heart failure
• ACS
• Heart muscle disease
• Pericardial disease
• Valvular heart disease
• Atrial fibrillation
• Pulmonary hypertension
• Myocarditis
• Cardiac surgery
• Congenital heart disease
• Cardioversion
• Advancing age
• Anemia
• Pulmonary embolism
• Sleep apnea
• Critical illness
• Sepsis
• Burns
• Toxic-metabolic insults
• Renal failure
Natriuretic Peptide Clearance
• BNP

• NPR
• Renal excretion
• Neprilysin

• NT-proBNP

• Less well understood

• Renal excretion partially responsible
Using natriuretic
peptides clinically
2. Know how to interpret them
How not to get burned: know the differential diagnosis!

For unexpectedly HIGH values:

• Heart failure • Cardioversion, ablation
• ACS • Advancing age
• Heart muscle disease • Anemia
• Pericardial disease • Pulmonary embolism
• Valvular heart disease • Sleep apnea
• Atrial fibrillation • Critical illness
• Pulmonary hypertension • Sepsis
• Myocarditis • Burns
• Cardiac surgery • Toxic-metabolic insults
• Congenital heart disease • Renal failure
How not to get burned: know the differential diagnosis!

For unexpectedly LOW values:

• Obesity
• HFpEF
• Mild acute heart failure
• Isolated right heart failure
• Partially treated heart failure
 Using natriuretic
peptides clinically
3. Know when and why to use them
 HF Clinical Practice Guidelines

Indication Class LOE

NPs for diagnosis1-3 I A
NPs for prognosis1-3 I A
NPs for predischarge risk assessment1-3 IIa B-NR
NPs to prevent HF onset1-3 IIa B-R
NPs to guide HF therapy4 IIb B
Fibrosis/injury markers for additive risk stratification4 IIb B-NR

LOE, level of evidence. 1. Yancy CW et al. J Am Coll Cardiol. 2017. doi: 10.1016/j.jaac.2017.04.025. 2. Yancy CW et al. Circulation. 2017. doi: 10.1161/CIR.0000000000000509. 3. Yancy CW et al. J Card Fail. 2017. doi: 10.1016/j.cardfail.2017.04.014. 4. Yancy CW, et al.
Circulation. 2013;e240-327.
 ICON-RELOADED Results: NT-proBNP

1.0

40000

p <.0001 0.8

30000
NT-proBNP (pg/mL)

0.6
Diagnostic Median NT-

Sensitivity
20000 Category proBNP
0.4
Patients without 98 pg/mL
10000
AHF
0.2
Patients with AHF 2844 pg/mL

0 0.0 AUC= 0.9148; 95% CI,0.8978-0.9317

ADHF (N=277) No ADHF (N=1184)

0.0 0.2 0.4 0.6 0.8 1.0

1 - Specificity

Januzzi, et al, J Am Coll Cardiol, 2018;71(11):1191-1200

ICON-RELOADED Results: Cost-effectiveness

• 14% fewer initial

hospitalizations
• 15% fewer admissions to
cardiology or ICU
• 30% reduction in
echocardiograms
• 26% fewer ED or hospital
readmissions

Siebert, et al, Submitted, 2020

 ICON-RELOADED Results: Cost-effectivess

• Use of NT-proBNP decreased the

average inpatient management costs
by a relative 10.4% ($20,247 vs.
$22,584) and reduced the total length
of stay in ED and hospital, yielding cost
savings of $2,337/pt
• NT-proBNP reduced SAEs by 5.9%
compared to clinical assessment alone

Siebert, et al, Submitted, 2020

 HF Clinical Practice Guidelines

Indication Class LOE

NPs for diagnosis1-3 I A
NPs for prognosis1-3 I A
NPs for predischarge risk assessment1-3 IIa B-NR
NPs to prevent HF onset1-3 IIa B-R
NPs to guide HF therapy4 IIb B
Fibrosis/injury markers for additive risk stratification4 IIb B-NR

LOE, level of evidence. 1. Yancy CW et al. J Am Coll Cardiol. 2017. doi: 10.1016/j.jaac.2017.04.025. 2. Yancy CW et al. Circulation. 2017. doi: 10.1161/CIR.0000000000000509. 3. Yancy CW et al. J Card Fail. 2017. doi:
10.1016/j.cardfail.2017.04.014. 4. Yancy CW, et al. Circulation. 2013;e240-327.
 One month change in NT-proBNP and outcomes

2.5

2.0

1.5

1.0
Hazard Ratio for Primary Outcome

0.5

-3 -2 -1 0 1 2
Log2 (One month NT-proBNP after randomization /
Baseline NT-proBNP)

Zile et al, JACC 2016

 Can NT-proBNP inform remodeling status?

• Triggers for NT-proBNP include

“forward” remodeling

✓ Stretch
✓ Activation of RAAS

• It remained unclear if serial

measurement of NT-proBNP
could inform changes in LA or LV
remodeling

Cao Z, Jia Y, and Zhu B. Int Jour Mol Science, 2019;20(8):1820

Results in context: Change in LV Structure and Function at 1
Year by NT-proBNP Reduction

EF (%) EDVi (ml/m2) ESVi (ml/m2)

13.35
11.68
10.02
8.35
6.69

-15.68
-17.34
-19.24
-21.03
-22.8
-24.71
-26.36
-28.4
-29.92
-32.09

ΔNT-proBNP (pg/ml): -1000 -2000 -3000 -4000 -5000

Daubert, et al, JACC Heart Failure, 2019

 Importance of biomarker testing for HF monitoring
Intensification 2–4 months Stabilization
(1–4 week cycles) ~3 months

Studies to Consider Initially:
(see full guidelines for details)
• BNP/NT-proBNP
• CBC, basic metabolic panel, liver
function, iron studies, thyroid studies,
HbA1c
• EKG
• Chest X-ray
• Echocardiogram
• Coronary angiogram, cardiac MRI,
biopsy, other imaging as appropriate
Serial Evaluation and Titration of End-intensification/ Assess response to therapy
Medications maintenance and cardiac remodeling
• Clinic visit with history symptoms, vitals, • Ongoing assessment • Repeat laboratory tests, for example,
exam, labs • Additional adjustments as BNP/NT-proBNP and basic metabolic
• If volume status requires treatment, adjust indicated panel
diuretics, follow up 1–2 weeks • Repeat objective data as • Repeat echocardiagram (or similar
• If euvolemic and stable, start/increase/switch needed to reestablish imaging modality for cardiac structure
GDMT, follow-up 1–2 weeks via phone or prognosis and function
repeat clinic visit with basic metabolic panel as • Repeat EKG
may be indicated • Consider EP referral for those eligible
• Repeat cycle until no further changes are possible for CRT or ICD
or tolerated

Lack of response/instability
Remember acronym to assist in decision making for referral to advanced heart failure specialist: I-NEED-HELP
I N E E D H E L P
IV inotropes NYHA IIIB/IV End-organ Ejection Defibrillator Hospitalisations Edema despite Low blood Prognostic medication
or persistently dysfunction fraction ≤ 35% shocks >1 escalating pressure, – progressive
elevated diuretics high heart intolerance or down
natriuretic peptides rate titration of GDMT

BNP, B type natriuretic peptide; HF, heart failure; NT-proBNP, N-terminal-pro-B type natriuretic peptide.
Yancy CW, et al. J Am Coll Cardiol. 2018;71:201–230.
 Operationalizing NP monitoring to enhance clinical
decision-making in chronic HF
• In recently decompensated patients, measure 1–2 weeks after
discharge (office or home).
• In stable ambulatory patients, measure every 3 months
• Stable concentrations <1000 pg/mL (NT-proBNP) or <100 pg/mL
(BNP): imaging and other testing may be deferred
• Elevated/rising concentrations: repeat imaging, further evaluations,
review medication/lifestyle program and adjust as appropriate
• Markedly elevated concentrations: Consider transplant referral,
consider diagnoses associated with “unexpectedly elevated”
NP (amyloidosis).

HF, heart failure; NT-pro-BNP, N-terminal pro-B type natriuretic peptide.

Yancy CW, et al. J Am Coll Cardiol. 2018;71:201–230.
Using natriuretic
peptides clinically
4. Recognize their
expanding potential
 HF Clinical Practice Guidelines

Indication Class LOE

NPs for diagnosis1-3 I A
NPs for prognosis1-3 I A
NPs for predischarge risk assessment1-3 IIa B-NR
NPs to prevent HF onset1-3 IIa B-R
NPs to guide HF therapy4 IIb B
Fibrosis/injury markers for additive risk stratification4 IIb B-NR

LOE, level of evidence. 1. Yancy CW et al. J Am Coll Cardiol. 2017. doi: 10.1016/j.jaac.2017.04.025. 2. Yancy CW et al. Circulation. 2017. doi: 10.1161/CIR.0000000000000509. 3. Yancy CW et al. J Card Fail. 2017. doi: 10.1016/j.cardfail.2017.04.014. 4. Yancy CW, et al.
Circulation. 2013;e240-327.
 NT-proBNP and prognosis after ADHF treatment

Salah, et al, Heart, 2014

NP Monitoring to Enhance Clinical Decision Making in AHF

• Two measurements:
• At presentation for diagnosis, triage, and prognostication.

• At the end of hospitalization to evaluate for treatment response and provide

hospital to home link.
✓ 30% drop is desirable, and lower is always better

✓ If baseline not available discharge NT-proBNP <4000 or BNP < 350 pg/mL is desirable

✓ Non-falling or rising values identify a patient at imminent risk for rehospitalization

and/or death
 HF Clinical Practice Guidelines

Indication Class LOE

NPs for diagnosis1-3 I A
NPs for prognosis1-3 I A
NPs for predischarge risk assessment1-3 IIa B-NR
NPs to prevent HF onset1-3 IIa B-R
NPs to guide HF therapy4 IIb B
Fibrosis/injury markers for additive risk stratification4 IIb B-NR

LOE, level of evidence. 1. Yancy CW et al. J Am Coll Cardiol. 2017. doi: 10.1016/j.jaac.2017.04.025. 2. Yancy CW et al. Circulation. 2017. doi: 10.1161/CIR.0000000000000509. 3. Yancy CW et al. J Card Fail. 2017. doi: 10.1016/j.cardfail.2017.04.014. 4. Yancy CW, et al.
Circulation. 2013;e240-327.
Elevated NPs predict onset of HF

• Patients with higher baseline risk for

HF may be a particularly rich target for
NP screening.

• This includes patients with DM,

hypertension/LVH, and ischemic heart
disease
STOP-HF Trial

Routine PCP care BNP-directed care

•Annual BNP not available In addition to routine PCP care,

annual BNP in all
to clinicians
If BNP >50 pg/ml at any time
• At least annual review by
PCP
•Shared-care

• Cardiology review only if • Cardiology review

requested by PCP • Echo-Doppler
• Other CV investigations
• CV nurse coaching
• Cardiology follow-up
 STOP HF Primary Endpoint

Ledwege et al, JAMA 2013

 Neurohormonal Therapy for Primary Prevention of CV Events in Patients With
Diabetes With Elevated NT-proBNP
The PONTIAC Trial investigated the preventive effect of neurohormonal therapy in high-
risk patients with diabetes with elevated NT-proBNP
Hospitalization or Death Due to
Cox Regression Models
Cardiac Disease
1.0 Treatment (n = 150)

Endpoint HR 95% CI P value

Primary Endpoint
Controls (n = 150)
Hospitalization or death due to
0.351 0.127-0.975 .04
cardiac disease
0.8 P=.035
All-cause hospitalizations 0.657 0.465-0.927 .02

Unplanned CV hospitalization
0.376 0.157-0.899 .03
or death

HF hospitalizations 0.140 0.017-1.137 .07

0.6
0 5 10 15 20 24

Patients (N = 300) with type 2 diabetes and elevated NT-proBNP (>125 pg/mL), but free of cardiac disease. Control group patients (n=150)
Months
were treated at 4 diabetes care units. Treatment group patients (n=150) were additionally treated at a cardiac outpatient clinic for the up-
titration of RAAS antagonists and beta-blockers.
PONTIAC, NT-proBNP Selected PreventiOn of cardiac eveNts in a populaTion of dIabetic patients without A history of Cardiac disease.
Huelsmann M et al. J Am Coll Cardiol. 2013;62:1365-1372.
Topics
•What’s new with:

→Troponin

→Natriuretic peptides