Troponin - Jacobi Medical Center

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Troponin
and other diagnostic tests
Rob Siegel, MD
Jacobi Cardiology
Learning Objectives
When to order troponin
 How to interpret troponin values
 Clarify troponin confusion
 Review DDx of troponin elevation

Case #1: In the ED
Chief complaint: Chest pain
 67 M with no prior cardiac history
 Risk factors are HTN
 Presents with two hours of
nonexertional epigastric pain radiating
to his chest; episode resolved
spontaneously 30 minutes before
reaching the ED. Nonpleuritic.

Case #1, continued
PMH: HTN, GERD
 PSH: Inguinal hernia, age 22
 Medication: , HCTZ 25mg PO daily,
Maalox Plus PRN
 NKDA
 SH: Quit tobacco 20 years ago. No E/D
 FH: Father had MI age 77, no other MI
in family, no CVA

Case #1, continued
136/72 P84 R24 SpO2=99%RA
 Pleasant, conversant, NAD
 JVP<8cm H2O, no bruits
 CTA, no crackles
 RRR, II/VI midsystolic murmur at LSB
 Warm extremities without edema

Case #1, continued
CXR: wnl
 EKG: normal sinus rhythm at 82, Twave inversions in III and aVF; no prior
EKG

Case #1, summarized
This is a patient with atypical chest pain,
and a somewhat low pre-test probability
of acute coronary syndrome
 (EKG is not completely normal, and the
patient has hypertension)

Case #1: What do you do?
1) Discharge home with outpatient
medical clinic follow-up
 2) Admit to telemetry; rule out for MI
with troponin; if rules out, obtain stress
test
 3) Stat cardiac catheterization

This will get more advanced
I promise. This case, and the next slide,
will sounds a little like kindergarten to
most of you.
 But there’s an important point here.
Please bear with me.

Troponin is a diagnostic test
You know how to interpret a diagnostic
test.
 You start with a pre-test probability.
 (If it’s really low or really high, you don’t
get the test.)
 If it’s intermediate, you get the test.
 Afterward, you have a post-test
probability. You act on the result.

Diagnostic Performance of Cardiac Troponin Assays at Presentation
This one is Jacobi’s
A diagnostic
test has a
receiveroperator
curve.
Reichlin T et al. N Engl J Med 2009;361:858-867
Reichlin T et al. N Engl J Med 2009;361:858-867
Troponin helps you diagnose one
condition.

And, with a couple of unimportant
exceptions, one condition only.

What is that condition?
The Most Important Point

Troponin is a diagnostic test

To help determine whether acute
coronary syndrome is present

It’s not really useful in other situations
(with a couple rare exceptions)
Acute Coronary Syndrome
(ACS)

Also known as coronary artery plaque
rupture

This is the condition we were worried
about in the case: We were concerned
that the patient could have ACS with
atypical symptoms
Acute coronary syndrome
Troponin was developed to help
rule out acute ACS
It was not developed for any other
purpose
 Many studies have validated its use in
this scenario
 When we use it to make other clinical
decisions, we’re using it for a sort of offlabel indication

NPV/PPV
Jacobi’s troponin
Reichlin T et al. N Engl J Med 2009;361:858-867
Your patient has a single negative
troponin value.
When should you check troponin again?
 (Remember, you’re trying to rule out
acute coronary syndrome.)

Reichlin T et al. N Engl J Med 2009;361:858-867
If negative at presentation, check troponin
again at least 4 hours after onset of symptoms
Your inpatient has ruled out.
When to check troponin again?

Unless the patient has an episode that
raises concern for ACS:
Do not check troponin again.
(If you do, you’re using the assay in a way
that nobody ever intended.)
Your inpatient has ruled in. When
to check troponin again?
It takes about a week for troponin level to return
to normal after ACS.
Short answer: Do not check again during
this hospitalization.

(Longer answer: If there is new concern for
ACS one week after ruling out, then check
again then.)
Congratulations!

This talk is complete. You now know
everything you need to know about the
clinical utility of troponin.

The rest of the talk will address
troponin-related information that does
not assist in clinical decision-making.
Troponin confusion hall of fame
“If the troponin is positive, that means
you need to start heparin.”
 “Isn’t there a new type of MI called a
‘Type 2 Myocardial Infarction,’ and this
is the same as demand ischemia?”
 “But where is the troponin coming from
if it’s not coming from the heart?”

Case #2
CC: Chest pain
 67 year-old man with HTN, DM, CHOL
 Notes one month of progressive angina.
Exercise tolerance was unlimited one
month ago; then began to develop
substernal chest pressure with exertion
with climbing five flights of stairs.

Case #2, continued
During the past month he gets chest
pressure with less and less exertion.
Yesterday he felt angina with climbing
one-half flight of stairs.
 This morning, while eating breakfast, he
developed angina at rest.
 He continues to have chest pain in the
ED despite receiving NTG from EMS.

Case #2, continued
PMH: HTN, CHOL, DM
 PSH: None
 Medication: Metformin, Lisinopril, ASA,
Simvastatin
 NKDA
 SH: No T/E/D
 FH: Father had MI age 57; no other
CAD; no history of CVA

Case #2, continued
118/70 P92 R24 SpO2=98% on 2L NC
 Pleasant, conversant, quiet
 JVP<8
 CTA, no crackles
 RRR, no murmur, S4
 No edema
 Guaiac negative brown stool

Case #2, continued
C7 and CBC are normal
 CXR is normal
 EKG is normal sinus rhythm,
downsloping ST segment depressions
in leads I, aVL, V5, and V6
 Troponin is pending

When to start heparin?
Single best answer:
1) If troponin I is greater than 0.1 g/L
 2) If troponin I is greater than 0.5 g/L
 3) If troponin I is greater than 5 g/L
 4) None of the above

ACS Spectrum
STEMI
 NSTEMI
 Unstable angina

Acute coronary syndrome
ACS Spectrum
STEMI (troponin doesn’t matter)
 NSTEMI (troponin is positive)
 Unstable angina (troponin is negative)

Treat all of the above with heparin unless
there is a contraindication to heparin
Unstable Angina v. NSTEMI
The only difference here is in the
terminlology (and in the troponin level)
 Treatment for the two conditions is
essentially the same

Case #2, review
Patient with multiple cardiac risk factors,
comes in with (very) typical history of
acute coronary syndrome, now with
chest pain at rest
 Troponin measurement has almost no
role in establishing the diagnosis,
because the diagnosis of ACS is
already essentially certain
 Give this patient heparin!

Case #3

Has many similarities to case #2, in
case #2 the decision-making was
simple, while in case #3 the decision
making is complex.
Case #3
CC: Chest pain
 67 year-old man with HTN, CHOL, PUD
 Notes one month of progressive angina.
Exercise tolerance was unlimited one
month ago; then began to develop
substernal chest pressure with exertion
with climbing five flights of stairs.

Case #3, continued
PMH: HTN, CHOL, PUD
 PSH: None
 Medication: HCTZ, Simvastatin,
Omeprazole
 NKDA
 SH: No T/E/D
 FH: Father had MI age 77; no other
CAD; no history of CVA

Case #3, continued
118/70 P108 R24 SpO2=98% on 2L NC
 Pleasant, conversant, pale
 JVP<8
 CTA, no crackles
 RRR, no murmur, S4
 No edema
 Guaiac positive black stool

Case #3, continued
C7 is normal
 CBC shows hemoglobin=6,
hematocrit=19, MCV=71
 CXR is normal
 EKG is sinus tachycardia, downsloping
ST segment depressions in leads I,
aVL, V5, and V6
 Troponin is pending

When to start heparin?
Single best answer:
1) If troponin I is greater than 0.1 g/L
 2) If troponin I is greater than 0.5 g/L
 3) If troponin I is greater than 5 g/L
 4) None of the above

Case #3: Summary
Patient presents with severe angina in
context of severe anemia with active
bleeding
 Most likely explanation for angina:
Demand ischemia, caused by anemia

(Patient cannot deliver enough oxygen
to myocardium due to anemia)
Cases 2 and 3 compared
Case 2
Case 3
Angina?
Yes
Yes
Ischemia?
Yes
Yes
Etiology?
ACS
Bleeding
Heparinize?
Yes
No!
Troponin?
+/-
+/-
Case #2 and 3: Take-home point
Do give heparin for unstable angina,
regardless of troponin
 Do not give heparin for troponin
elevation alone,
unless there’s another reason to give
heparin


In case #3, heparin could be lethal
NPV/PPV
Reichlin T et al. N Engl J Med 2009;361:858-867
Troponin confusion hall of fame
“If the troponin is positive, that means
you need to start heparin.”
 “Isn’t there a new type of MI called a
‘Type 2 Myocardial Infarction,’ and this
is the same as demand ischemia?”
 “But where is the troponin coming from
if it’s not coming from the heart?”

“Type 2 Myocardial Infarction”
This is not a clinically helpful concept
 It does not help you think through how
to manage your patient

Slightly useful in research studies
 Very useful to the patient billing office-we get reimbursed well for MI

Myocardial Infarction Types

Type 1 (ACS)
“Spontaneous myocardial infarction related to
ischaemia due to a primary coronary event
such as plaque erosion and/or rupture,
fissuring, or dissection.”
 Type 2
“Myocardial infarction secondary to ischaemia
due to either increased oxygen demand or
decreased supply, e.g. coronary artery
spasm, coronary embolism, anaemia,
arrhythmias, hypertension, or hypotension.”
MI Types, Continued

Type 3 (ACS that kills you before you can
measure troponin)
“Sudden unexpected cardiac death, including
cardiac arrest, often with symptoms
suggestive of myocardial ischaemia,
accompanied by presumably new ST
elevation, or new LBBB, or evidence of fresh
thrombus in a coronary artery by angiography
and/or at autopsy, but death occurring before
blood samples could be obtained, or at a time
before the appearance of cardiac biomarkers
in the blood.”
Don’t Memorize This

Type 4a
Myocardial infarction associated with PCI
 Type 4b
Myocardial infarction associated with stent
thrombosis as documented by angiography or
at autopsy
 Type 5
Myocardial infarction associated with CABG
Universal Definition of Myocardial Infarction Kristian Thygesen*, Joseph S. Alpert,
Harvey D. White on behalf of the Joint ESC/ACCF/AHA/WHF Task Force for the
Redefinition of Myocardial Infarction. J Am Coll Cardiol, 2007; 50: 2173-2195.
Troponin confusion hall of fame
“If the troponin is positive, that means
you need to start heparin.”
 “Isn’t there a new type of MI called a
‘Type 2 Myocardial Infarction,’ and this
is the same as demand ischemia?”
 “But where is the troponin coming from
if it’s not coming from the heart?”

Differential diagnosis
So now you have a troponin level that is
elevated. Your pre-test probability for
ACS was very low; troponin should not
have been ordered.
 Now you’re in a clinical scenario that the
troponin-validation studies do not
address. What to do?

Don’t memorize this


Cardiac diseases and interventions
Cardiac amyloidosis/Cardiac contusion/Cardiac
surgery/Cardioversion and implantable cardioverter defibrillator
shocks/Closure of atrial septal defects/Coronary
vasospasm/Dilated cardiomyopathy/Heart failure/Hypertrophic
cardiomyopathy/Myocarditis/Percutaneous coronary
intervention/Post cardiac transplantation/Radiofrequency
ablation/Supraventricular tachycardia
Non-cardiac diseases
Critically ill patients/High dose chemotherapy/Primary
pulmonary hypertension/Pulmonary embolism/Renal
failure/Subarachnoid haemorrhage/Scorpion
envenoming/Sepsis and septic shock/Stroke/Ultra-endurance
exercise (marathon)
Peter Ammann, Matthias Pfisterer, Thomas Fehr, Hans Rickli. Raised cardiac
troponins: Causes extend beyond acute coronary syndromes. BMJ. 2004 May 1;
328(7447): 1028-1029.
Siegel 6-category Troponin DDx
Thrombosis
 Trauma
 Demand
 “Sick”
 Brain
 Annoying

Thrombosis
Pulmonary embolism
Troponin is elevated in 30-50% of cases
of clinically proven PE
 Acute Coronary Syndrome

Give heparin!
Trauma
Electrical
Even a single ICD shock can cause
troponin elevation

Mechanical
Surgery. Cardiac ablation procedures.
Trauma.
(Check troponin after chest trauma.)

Supply/Demand Mismatch
Increased myocardial oxygen demand
Tachycardia, hypertrophy, fever, surgery

Decreased myocardial oxygen supply
Hypoxia, anemia, hypotension

Demand, continued: Tachycardia
Tachycardia alone has been implicated as a
cause of troponin elevation in case series.
 In one series of 21 patients with elevated cTnI
levels and normal coronary angiograms,
tachycardia was determined to be the
explanation of the troponin elevation in six
patients.
 A second series described four patients with
troponin elevations after episodes of
supraventricular tachycardia (SVT), who had
no evidence of CHD.
Demand, continued: Tachycardia

Myocardial troponin can be released as
a consequence of tachycardia alone in
the absence of myodepressive factors,
inflammatory mediators, and CHD.
Bakshi TK; Choo MK; Edwards CC; Scott AG; Hart HH;
Armstrong GP. Causes of elevated troponin I with a normal
coronary angiogram. Intern Med J 2002 Nov;32(11):520-5.
Demand, continued: Hypertrophy

In a series of 74 consecutive patients without
clinical evidence of active myocardial
ischemia referred for routine
echocardiography, seven of 25 patients in
the tertile with the greatest LV mass had
an elevated cTnI. In contrast, one patient in
the intermediate range, and none of patients
in the lowest tertile had elevated troponin.
Hamwi, SM, Sharma, AK, Weissman, NJ, et al. Troponin-I
elevation in patients with increased left ventricular mass.
Am J Cardiol 2003; 92:88
Demand, continued: Hypertrophy

LVH can lead to occult subendocardial
ischemia via increased oxygen demand from
increased muscle mass, coupled with
decreased flow reserve due to remodeled
coronary microcirculation.
 Similar observations have been made in the
setting of aortic valve disease.
Cardiac troponin I in aortic valve disease. Nunes JP; Mota Garcia
JM; Farinha RM; Carlos Silva J; Magalhaes D; Vidal Pinheiro L;
Abreu Lima C. Int J Cardiol 2003 Jun;89(2-3):281-5.
“Sick”
Sepsis
Not only does this cause demand
ischemia, it may also cause degradation
of intramyocyte troponin molecules,
allowing them to permeate the cell
membrane (hypothetical)
 Autoimmune/infiltrative
Myocarditis, amyloid

Brain

Subarachnoid hemorrhage (SAH)
 Acute CVA
Troponin is elevated in about 27% of patients
with acute stroke, and in SAH case series.
Probably due to catecholinergic surge; autopsy
studies demonstrate myocardial band necrosis
in some of these patients
Trooyen M, Indredavik B, Rossvoll O, Slordahl SA. [Myocardial injury in acute stroke assessed by troponin I] Tidsskr
Nor Laegeforen 2001 Feb 10;121(4):421-5.
Tung, P, Kopelnik, A, Banki, N, et al. Predictors of neurocardiogenic injury after subarachnoid hemorrhage. Stroke
2004; 35:548.
Naidech, AM, Kreiter, KT, Janjua, N, et al. Cardiac troponin elevation, cardiovascular morbidity, and outcome after
subarachnoid hemorrhage. Circulation 2005; 112:2851.
Homma, S, Grahame-Clarke, C. Editorial comment--myocardial damage in patients with subarachnoid hemorrhage.
Stroke 2004; 35:552.
Annoying

Lab error
Proximity to mice

Chronic Kidney Disease
Can have positive troponin for years. Also have
poor prognosis and CAD, too. If they also get
atypical chest pain, should we cath these
people or not?
Siegel 6-category Troponin DDx
Thrombosis (ACS, PE)
 Trauma (Electrical, mechanical)
 Demand (Demand, supply)
 “Sick” (Sepsis, immune/infiltrative)
 Brain (Large CVA, SAH)
 Annoying (Lab error, CKD)

Troponin without ACS
It’s like a positive RPR without syphilis:
 It can be a hint that you’re missing a
diagnosis.
 It can also end up being clinically
useless
 There is no clear evaluation strategy,
other than to think through the DDx of
elevated troponin and see if it helps
improve your patient’s diagnosis
Troponin without ACS, cont.
When you get this, should you look for or
treat CAD?
• Get a stress test?
• Get a cath?
• Change your LDL treatment goal?
Troponin without ACS, cont.
"There are currently no data from randomized,
controlled trials evaluating the efficacy of
therapies aimed at reducing risk in patients
with troponin elevations in the absence of an
ACS." -Up-To-Date
That said, you probably should give aspirin
and beta blockers--in case you’re missing an
ACS, the benefit is huge and the risks of
these treatments are minimal.
• (Quadramed recommends this.)
•
Troponin confusion hall of fame
“If the troponin is positive, that means
you need to start heparin.”
 “Isn’t there a new type of MI called a
‘Type 2 Myocardial Infarction,’ and this
is the same as demand ischemia?”
 “But where is the troponin coming from
if it’s not coming from the heart?”

Myocyte Necrosis is not
necessary to make troponin
In rat cardiomyocytes, only 15 minutes
of mild ischemia has been shown to be
enough to cause troponin release
 This interval is too short to induce cell
death

McDonough JL, Arrell DK, Van Eyk JE. Troponin I degradation and
covalent complex formation accompanies myocardial
ischemia/reperfusion injury. Circ Res 1999;84: 9-20.
Increased preload alone can
cause troponin release.
Troponin degradation has been
demonstrated with increased preload,
independent of myocardial ischemia, in
isolated rat hearts.
 Preload induces troponin I degradation
independently of myocardial ischemia.

Feng J; Schaus BJ; Fallavollita JA; Lee TC; Canty JM Jr.
Preload induces troponin I degradation independently of
myocardial ischemia. Circulation 2001 Apr 24;103(16):2035-7.
Causes of Troponin Elevation
where Heparin Can Be Lethal







Demand ischemia from anemia/hypovolemia
from blood loss--can appear clinically similar
to ACS
Pericarditis
Subarachnoid hemorrhage
Large CVA
Traumatic cardiac contusion
Thoracic aortic dissection
All of the above can present with EKG
changes; list is not complete
Degree of troponin elevation
as an aid to diagnosis
“This cannot be demand ischemia alone.
The troponin level is too high.”
 If there is any clinical study showing the
maximum troponin level achievable in any
condition, I am not aware of it.
(With the exception of ICD shocks, where we
think we know the upper limit.)
 STEMI can present with surprisingly low
troponin values.
Degree of troponin elevation
as an aid to prognosis
In almost every study,
In a broad array of conditions,

The higher the peak troponin value, the
worse the mortality.
Has been demonstrated in studies of
ACS, PE, CVA, ESRD, sepsis

Troponin Predicts Mortality
Antman TM, Tenasijevic MJ, Thompson B, et al. Cardiac-specific
troponin I levels to predict the risk of mortality in patients with
acute coronary syndromes. N Engl J Med 1996;335:1342-1349.
Why is troponin better than CK?

Because it is more accurate than CK, and
also more sensitive than CK-MB for detecting
ACS.
 (However, troponin stays elevated longer,
which is a drawback.)
The figure on the following slide comes from:
Omland T, de Lemos JA, Sabatine MS, et al. A sensitive cardiac
troponin T assay in stable coronary artery disease. N Engl J
Med 2009;361:2538-2547.
ROC troponin/myoglobin/CKCK-MB
Time course of serum markers
in acute myocardial infarction
Larue C, Calzolari C, Bertinchant JP, Leclercq F, Grolleau R, Pau B.
Cardiac-specific immunoenzymometric assay of troponin I in the
early phase of acute myocardial infarction.
Clin Chem. 1993;39:972–979.
QuickTime™ and a
TIFF (LZW) decompressor
are needed to see this picture.
Thank you.
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