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CLINICIANS CORNER
JAMA. 2013;309(21):2262-2269
of MI, a consensus document representing multiple international cardiology societies, requires an elevated troponin level combined with symptoms
or signs of ischemia for the diagnosis
of MI (BOX 1).4 In addition to requiring at least 1 troponin value above the
MI diagnostic threshold, an increase or
decrease in troponin levels over serial
measurement is necessary to meet the
MI definition. The decision limit for MI
is set by consensus at the 99th percentile value of a healthy normal population and varies with each troponin
assay.
The universal definition recognizes
the distinction between classic (type
1) MI, caused by ACS with atherosclerotic plaque rupture or erosion and
Myofibrillar troponins
Myosin
Cardiomyocytes
TnC
cTnT
cTnI
Actin
Tropomyosin
Cytosolic troponins
cTnI
cTnT
Release of
cardiac troponins into
the bloodstream
BLOOD
VESSEL
9 hours, shorter intervals are appropriate among individuals with a low probability of MI who are also at low risk
for death or ischemic complications. An
innovative approach proposed by Than
et al9 incorporated assessment of pretest probability for MI and risk for complications using the Thrombolysis in
Myocardial Infarction (TIMI) risk score,
together with ECG findings and serial
measurement of cTnI levels at 0 and 2
hours. Among 1975 patients presenting with suspected ACS, 20% were classified as at low risk, defined prospectively as a TIMI risk score of 0, the
absence of ischemic ECG changes, and
cTnI level below the MI detection
threshold at both time points. The negative predictive value (NPV) was greater
than 99% in the low-risk group, suggesting that this expedited algorithm,
or a similar one, may allow rapid discharge of low-risk individuals without additional testing.
Risk Stratification and Therapeutic
Decision Making in Suspected ACS
Yes
Type 1 MI
Type 2 MI
No
Nonischemic acute
myocardial injury
Pulmonary embolism,
acute heart failure, etca
Consider echocardiogram
Correct precipitant
This algorithm is based on available literature19,28 but has not been separately validated. ECG indicates electrocardiogram; MI, myocardial infarction.
a See Box 2 for more detail.
Fourth-Generation
0.90 (0.86-0.94)
10
cTnI b
Highly
Sensitive
0.96 (0.94-0.98)
14
Contemporary
Sensitive
0.92 (0.90-0.94)
32
Highly
Sensitive
0.96 (0.95-0.97)
30
35
13
32
5.2
83 (76-90)
95 (90-98)
79 (75-84)
82 (77-87)
Specificity, %
Positive predictive
value, %
93 (91-95)
72 (64-79)
80 (77-83)
50 (43-56)
95 (93-96)
81 (76-85)
92 (90-94)
75 (70-80)
Negative predictive
value, %
97 (95-98)
99 (97-100)
94 (92-95)
95 (93-96)
Abbreviations: AUC, area under the receiver operating characteristic curve; cTnI, cardiac troponin I; cTnT, cardiac troponin
T; CV, coefficient of variation.
a Data for the comparisons of the Roche fourth-generation cTnT assay vs Roche highly sensitive cTnT assay are abstracted from Reichlin et al.7
b Data for comparisons of the contemporary sensitive (Abbott Architect STAT cTnI) assay vs highly sensitive (Abbott Architect hs-cTnI) assay are abstracted from Keller et al.33
and anxiety for patients and clinicians, are likely to be greater with the
highly sensitive assays.
2266
The development of highly sensitive assays has expanded the possible applications of troponin testing, including
potentially to the outpatient office visit.
With the highly sensitive assay, cTnT
can be detected at very low concentrations in more than 90% of outpatients
with stable chronic heart failure47 or
chronic CAD.48 In these chronic conditions, dose-dependent associations
have been observed between both cTnT
and cTnI and the subsequent risk for
death and heart failure, at levels well
below the detection threshold of standard assays.47-49
More recently, population screening with highly sensitive cTnT assays
was assessed in 3 large epidemiologic
cohorts totaling more than 17 500 individuals. The prevalence of detectable cTnT (3 ng/L) with the highly
sensitive assay ranged from 25% in the
Dallas Heart Study (ages 30-65 years)50
to 66.5% in the ARIC (Atherosclerosis
Risk in Communities) study (ages
54-74 years)39 and 66.2% in the CHS
(Cardiovascular Health Study) (ages
65 years).38 Concentrations of cTnT
increased with age and were higher in
men, African Americans, and individuals with CKD. Cardiac troponin T demonstrated strong associations with
pathological cardiac remodeling, in that
levels increased in parallel with the
presence and severity of left ventricular hypertrophy and left ventricular systolic dysfunction.50 Of interest is that
prior MI, angina, and coronary calcium were not associated with detectable levels of cTnT.
In each population-based study,
higher cTnT level was associated with
all-cause and cardiovascular mortality
and with incident heart failure,38,39,50,51
findings that remained significant after adjustment for traditional risk factors, renal function, and concentrations of N-terminal pro-brain natriuretic
peptide (NT-proBNP) and highsensitivity C-reactive protein (CRP).
When added to traditional risk assessment models, cTnT improved metrics
JAMA, June 5, 2013Vol 309, No. 21 2267
of discrimination and risk classification, performing at least as well as NTproBNP and outperforming highsensitivity CRP.38,39,50 Although cTnT
was associated with coronary heart disease events in the ARIC study, the magnitude of association was weaker than
for death and heart failure events.39
In a recent analysis from the Framingham Offspring Study incorporating a
novel highly sensitive cTnI assay, the proportion of adults with detectable cTnI
levels was 81%; in that study, higher cTnI
levels were associated with higher rates
death and heart failure but not MI,52 findings similar to those reported above for
highly sensitive cTnT assays.
In the CHS, approximately twothirds of individuals underwent a follow-up cTnT measurement 2 to 3 years
after the baseline measurement. In
analyses adjusting for baseline cTnT
levels as well as other risk predictors,
increases in cTnT level of 50% or more
during follow-up identified individuals at increased subsequent risk for
death and heart failure, with decreases in cTnT level associated with
lower risk. 38 This observation suggests that risk reflected by higher troponin concentrations may be modifiable. However, to date, only limited data
are available regarding the factors that
might favorably influence troponin levels in the population. An exploratory
analysis from the CHS demonstrated
that higher levels of baseline physical
activity were associated with a lower
probability of increased cTnT levels
over follow-up.53 In the ARIC study,
higher hemoglobin A1c levels (even
those below the diagnostic range for
diabetes) were associated with higher
cTnT levels measured years later.54
Much work still needs to be done before highly sensitive troponin assays can
be considered in the outpatient setting. Additional research is needed to
identify treatments that prevent additional cardiac injury and modify risk associated with elevated troponin levels. Although structural heart disease
and CKD explain some of the variation in troponin levels, many other
known and unknown factors contrib2268