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Accepted Manuscript

Title: Type 1 and 2 Myocardial Infarction and Myocardial Injury: Clinical


Transition to High-Sensitivity Cardiac Troponin I

Author: Yader Sandoval, Stephen W. Smith, Anne Sexter, Sarah E. Thordsen,


Charles A. Bruen, Michelle D. Carlson, Kenneth W. Dodd, Brian E. Driver,
Yan Hu, Katherine Jacoby, Benjamin K. Johnson, Sara A. Love, Johanna C.
Moore, Karen Schulz, Nathaniel L. Scott, Fred S. Apple

PII: S0002-9343(17)30716-7
DOI: http://dx.doi.org/doi: 10.1016/j.amjmed.2017.05.049
Reference: AJM 14183

To appear in: The American Journal of Medicine

Please cite this article as: Yader Sandoval, Stephen W. Smith, Anne Sexter, Sarah E. Thordsen,
Charles A. Bruen, Michelle D. Carlson, Kenneth W. Dodd, Brian E. Driver, Yan Hu, Katherine
Jacoby, Benjamin K. Johnson, Sara A. Love, Johanna C. Moore, Karen Schulz, Nathaniel L.
Scott, Fred S. Apple, Type 1 and 2 Myocardial Infarction and Myocardial Injury: Clinical
Transition to High-Sensitivity Cardiac Troponin I, The American Journal of Medicine (2017),
http://dx.doi.org/doi: 10.1016/j.amjmed.2017.05.049.

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Type 1 and 2 Myocardial Infarction and Myocardial Injury: Clinical Transition to

High-Sensitivity Cardiac Troponin I

Authors: Yader Sandoval1, MD, Stephen W. Smith2-3, MD, Anne Sexter, MPH, Sarah E.

Thordsen1, MD, Charles A. Bruen2,4, MD, Michelle D. Carlson1, MD, Kenneth W. Dodd2,4, MD,

Brian E. Driver2, MD, Yan Hu5, PhD Katherine Jacoby2,4, MD, Benjamin K. Johnson1, MD, Sara

A. Love6, PhD, Johanna C. Moore2, MD, Karen Schulz5, DC, Nathaniel L. Scott2,4, MD, Fred S.

Apple5,6, PhD

Affiliations:

1. Division of Cardiology, Hennepin County Medical Center and Minneapolis Heart Institute,

Abbott Northwestern Hospital, Minneapolis, MN, USA.

2. Department of Emergency Medicine, Hennepin County Medical Center, Minneapolis,

Minnesota, USA.

3. Department of Emergency Medicine, University of Minnesota, Minneapolis, MN, USA.

4. Minneapolis Medical Research Foundation, Minneapolis, MN, USA.

5. Department of Medicine, Hennepin County Medical Center, Minneapolis, MN, USA.

6. Department of Laboratory Medicine and Pathology, Hennepin County Medical Center and

University of Minnesota, Minneapolis, MN, USA

Total word count: 2,996 (limit 3000, including abstract, text, acknowledgements).

Clinical significance: 68 (limit 70). Abstract: 250 (limit 250).

References: 17. Tables: 2. Figures: 6

Corresponding author: Fred S. Apple, PhD.

Telephone: (612) 873-3324. Email: apple004@umn.edu. Hennepin County Medical Center,

Clinical Laboratories P4, 701 Park Avenue, Minneapolis, MN 55415, USA.

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Funding source: UTROPIA study (NCT02060760); partially funded through a grant

from a) Abbott Diagnostics, who had no role in the design and conduction of the study;

including data collection, management, analysis, and interpretation of the data; and

preparation, review, or approval of the final manuscript; and b) the Minneapolis Medical

Research Foundation.

Conflict of interest (s): Stephen W. Smith Consultant: Siemens. Sara A. Love

Research PI through Minneapolis Medical Research Foundation (MMRF) not salaried:

Biokit, Hytest Ltd., Instrumentation Laboratory; Other: Editorial Board Journal of Applied

Laboratory Medicine. Fred S. Apple Consultant: Phillips Health Incubator, Metanomics

Healthcare; Board of Directors, HyTest Ltd.; Honorarium: Instrumentation Laboratory,

Abbott Diagnostics; Research PI through Minneapolis Medical Research Foundation

(MMRF) not salaried: Abbott Diagnostics, Roche Diagnostics, Siemens Healthcare,

Alere, Ortho-Clinical Diagnostics, Becton Dickinson, Beckman Coulter, Abbott POC,

Davita, Amgen; Other: Associate Editor Clinical Chemistry. All other authors have

nothing to disclose.

All authors had access to the data and a role in writing the manuscript.

Article type: Clinical research study.

Keywords: myocardial infarction, myocardial injury, cardiac troponin

Running head: Type 1 and 2 Myocardial Infarction and Myocardial Injury

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CLINICAL SIGNIFICANCE

Cardiac troponin I increases occur in approximately 1/3 of patients, with only

15% due to type 1 myocardial infarction.

Compared to patients without myonecrosis, type 2 myocardial infarction and

myocardial injury have worse short-term outcomes, with mortality rates >20% at

2 years.

Transitioning in clinical practice from a contemporary to a high-sensitivity cardiac

troponin I assay does not lead to more cases of myocardial injury or myocardial

infarction.

ABSTRACT

Background: Studies addressing patients with type 2 myocardial infarction and

myocardial injury, including the impact of using high-sensitivity (hs) cardiac troponin

(cTn) assays on their incidence are needed.

Methods: Prospective, observational US cohort study. Consecutive emergency

department patients with serial cTnI measurements. Outcomes included 180-day

mortality and major adverse cardiac events, including 2-year follow-up for those with

myonecrosis.

Results: Among 1,640 patients, using a contemporary cTnI assay, 30% (n=497) had 1

cTnI >99th percentile; with 4.7% (n=77), 8.5% (n=140) and 17% (n=280) classified as

type 1 myocardial infarction, type 2 myocardial infarction and myocardial injury,

respectively. Compared to patients without myonecrosis, 180-day mortality was higher

for type 2 myocardial infarction (4% vs. 13%, p<0.0001) (adjusted HR 2.7, 95% CI 1.6-

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4.8, p=0.0005) and myocardial injury (4% vs. 11%, p<0.0001) (adjusted HR 1.8, 95% CI

1.1-3.0, p=0.02), both with mortality >20% at 2-years. Predictors of 2-year mortality for

type 2 myocardial infarction included age, congestive heart failure, and beta-blockers.

Relative to the contemporary cTnI assay, hs-cTnI had less myonecrosis (30% vs. 26%,

p=0.003) and acute myocardial infarction (13.2% vs. 10.8%, p=0.032), including fewer

type 2 myocardial infarctions (8.5% vs. 6.3, p=0.01) with no difference in myocardial

injury (17% vs. 15%, p=0.1).

Conclusions: cTnI increases are encountered in approximately a third of patients, the

majority due to non-atherothrombotic conditions. Compared to patients without

myonecrosis, type 2 myocardial infarction and myocardial injury have worse short-term

outcomes, with mortality rates >20% at 2 years. hs-cTnI assay does not lead to more

myocardial injury or infarction.

Cardiac troponin (cTn) measurements are central for ruling in and out acute myocardial

infarction1. With improved analytical sensitivity of cTn assays, clinicians are often

challenged with determining whether cTn increases are due to acute myocardial

infarction or myocardial injury2-11. Among those with myocardial infarction, type 1 and 2

myocardial infarction have received the most attention due to their incidence and

prognosis, as well as potentially distinct therapeutic implications based on the presence

or absence of atherothrombosis4-11.

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The goals of the present study were three-fold. First, we describe the incidence,

clinical features, management, and outcomes of patients with type 1 and 2 myocardial

infarction and myocardial injury. Second, we identified predictors of long-term mortality

for type 2 myocardial infarction and myocardial injury. Third, we determined the impact

on incidences when a using high-sensitivity (hs) cTnI assay.

METHODS

Study design and population

Following institutional review board approval, we prospectively included consecutive,

unselected patients presenting to the emergency department in whom initial pre-set

serial cTnI measurements at 0, 3, 6 and 9 hours (h), were ordered on clinical indication

at Hennepin County Medical Center (Minneapolis, MN, USA) to rule-in and rule-out

acute myocardial infarction (Use of TROPonin In Acute coronary syndromes

[UTROPIA], NCT02060760). For inclusion, patients needed a baseline cTnI at

presentation and at least one additional cTnI within 24h of presentation before

discharge, and at least one 12-lead electrocardiogram (ECG). Exclusion criteria were:

<18 years old, pregnancy, trauma, declined to participate, did not present through the

emergency department, or transferred from an outside hospital. For patients with more

than one presentation during the study period, we included only the first. Management

and outcomes analyses are based on the contemporary cTnI results as such were used

by providers for clinical decision-making at the time of study.

Cardiac Troponin I Assays

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Fresh ethylenediaminetetraacetic acid plasma samples were measured with both the

contemporary cTnI (clinically used) and hs-cTnI (investigational) assays on the Abbott

ARCHITECT i1000SR or i2000SR analyzers. For cTnI, the 99th percentile was 0.030 g/L.

The coefficient of variation was 18.5% at 0.028 g/L. For hs-cTnI, sex-specific 99th

percentiles were: women 16 ng/L and men 34 ng/L. The coefficient of variation was

<20% at 1.9 ng/L10,12.

Event Adjudication

All cases with at least one cTnI value >99th percentile were adjudicated according to the

Third Universal Definition of Myocardial Infarction1 by two clinicians following review of

all available medical records including ECG, echocardiography, angiography, cTnI

results and clinical presentation. Cases with an adjudication discrepancy were reviewed

and adjudicated by a third senior clinician. All cases were adjudicated twice,

independently using cTnI and hs-cTnI results separately, with adjudicators blinded to

the other adjudication process and alternate cTnI results. Using the contemporary cTnI,

a rise and/or fall in cTnI with at least one value >99th percentile was used to support the

diagnosis of acute myocardial infarction. A concentration change of at least >20% was

used to guide the adjudication using the contemporary cTnI assay. To guide

adjudication using hs-cTnI, an algorithm based on biological variation was followed to

ensure that changes within biological variation were not deemed abnormal 10. If the initial

hs-cTnI was <99th percentile, then a rise >69% and/or fall of >41% on serial sampling

were used to suggest a significant change. Conversely, if the initial hs-cTnI was >99th

percentile, then a change >20% was used.

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The term myocardial necrosis is used as follows: a) without myocardial necrosis

(serial measurements 99th percentile) or b) with myocardial necrosis (at least one

measurement >99th percentile). For the diagnosis of acute myocardial infarction, a rise

and/or fall with at least one value >99th percentile occurring in appropriate clinical

circumstances consistent with acute myocardial ischemia was required, plus at least

one additional myocardial infarction criteria1. Type 1 myocardial infarction was defined

as myocardial infarction related to atherosclerotic plaque rupture, ulceration, fissuring,

erosion, or dissection with resulting intraluminal thrombus1. Type 2 myocardial infarction

was defined as myocardial infarction secondary to an ischemic imbalance between

myocardial oxygen supply and/or demand not due to atherothrombosis, and was

adjudicated following the use of broad criteria9, an approach in which adjudicators

evaluate all contributing supply/demand variables and give a diagnosis of type 2

myocardial infarction without applying strict parameters1,7,9. For type 2 myocardial

infarction to be adjudicated, cases were required to include objective evidence or

documentation of supply/demand imbalance. Myocardial injury was defined as any cTnI

increase >99th percentile that was not adjudicated as myocardial infarction.

Outcomes

180-day outcomes examined included all-cause mortality (including events occurring at

the index hospitalization) and major adverse cardiac events defined as post-discharge:

death, recurrent myocardial infarction or unstable angina, revascularization, or

congestive heart failure. For those with myonecrosis, 2-year mortality follow-up was

performed.

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Statistical Analyses

Categorical variables were compared using Pearsons chi-square and Fishers exact

test where 50% of cells were less than 5. Continuous variables were compared using

the F-test. Cumulative survival curves were plotted using the Kaplan-Meier method and

compared between groups using the log-rank test. A multivariate Cox proportional

hazards model adjusted for age, congestive heart failure and estimated glomerular

filtration rate (eGFR > or < 60 mL/min/1.73m2) was used to determine the independent

contribution to mortality and major adverse cardiac events at 180-days. Predictors of

long-term mortality for type 2 myocardial infarction and myocardial injury were

determined by Cox proportional hazards regression. Univariate Cox regression

analyses were utilized to determine the impact on 2-year mortality in participants with

type 2 myocardial infarction and myocardial injury. Variables that were independent

predictors of 2-year mortality at the 0.1 significance level for type 2 myocardial infarction

or myocardial injury were included in a multivariate adjusted Cox regression model and

plotted on a Forest plot. Hazard ratios (HRs) with their respective 95% confidence

intervals (CI) are presented. Concordance between the hs-cTnI and cTnI assays was

evaluated using kappa statistics with respective 95% CIs. All tests were 2-sided and

statistical significance accepted at p<0.05. Statistical analyses were performed using

SAS version 9.4.

RESULTS

1,640 patients were included. Using the contemporary cTnI assay, 30% (n=497) of

patients had 1 cTnI >99th percentile; with 17% (n=280) classified as myocardial injury,

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4.7% (n=77) as type 1 myocardial infarction, and 8.5% (n=140) as type 2 myocardial

infarction.

Baseline characteristics are shown in Table 1 and Supplemental Table 1.

Patients with type 1 myocardial infarction presented more often with chest discomfort

than patients with type 2 myocardial infarction. They were also more likely to have

dyslipidemia, coronary artery disease, prior myocardial infarction, and prior

percutaneous coronary intervention, and had significantly higher baseline and maximum

cTnI concentrations than patients with type 2 myocardial infarction.

Cardiology consultations, transthoracic and stress echocardiography, and

coronary angiography were more frequently performed in type 1 myocardial infarction

than type 2 myocardial infarction (Supplemental Table 2). Among those undergoing

coronary angiography, type 1 myocardial infarction had higher rates of coronary artery

disease (91% vs. 54%, p<0.0001), with such patients more likely to undergo

revascularization than patients with type 2 myocardial infarction.

No differences existed among medications being taken prior to admission

(Supplemental Table 3). However, at discharge, compared to type 2 myocardial

infarction, patients with type 1 myocardial infarction were more likely to receive aspirin,

clopidogrel, statins, and angiotensin-converting enzyme inhibitors (ACEI) (Supplemental

Table 4). During the initial 24h, compared to type 2 myocardial infarction, patients with

type 1 myocardial infarction were also more likely to receive aspirin, heparin and

clopidogrel; albeit, antiplatelet and/or anticoagulant medications were still frequently

used in both type 2 myocardial infarction and myocardial injury (Supplemental Table 5).

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The most common determinants leading to type 2 myocardial infarction were:

tachyarrhythmia, hypertension, respiratory failure, and shock (Supplemental Table 6).

The most common etiologies for myocardial injury were: renal failure, congestive heart

failure, and neurological conditions (Supplemental Table 7).

Outcomes

At 180-days, all-cause mortality was 4%, 8%, 13% and 11% for patients without

myonecrosis, type 1 myocardial infarction, type 2 myocardial infarction and myocardial

injury, respectively (Supplemental Table 8). Compared to patients without myonecrosis,

type 2 myocardial infarction (4% vs. 13%, p<0.0001) (adjusted HR 2.7, 95% CI: 1.6-4.8,

p=0.0005) and myocardial injury (4% vs. 11%, p<0.0001) (adjusted HR 1.8, 95% CI:

1.1-3.0, p=0.02) had a higher mortality at 180-days (Figures 1 and 2). No difference was

observed compared to type 1 myocardial infarction (4% vs. 8%, p=0.12). Similarly,

compared to patients without myonecrosis, type 2 myocardial infarction (5% vs. 16%,

p<0.0001) (adjusted HR 2.2, 95% CI 1.4-3.7, p=0.001) and myocardial injury (5% vs.

19%, p<0.0001) (adjusted HR 2.2, 95% CI 1.4-3.2, p=0.0002) had a higher post

discharge major adverse cardiac events rate, with no difference observed compared to

type 1 myocardial infarction (5% vs. 10%, p=0.07).

No statistical differences existed at 180-days for all-cause mortality and post

discharge major adverse cardiac events between type 1 myocardial infarction and type

2 myocardial infarction or type 2 myocardial infarction and myocardial injury

(Supplemental Table 8). At 2-years, all-cause mortality for type 1 myocardial infarction,

type 2 myocardial infarction and myocardial injury was 16%, 22% and 26%, respectively

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(Figure 3), with no differences observed between type 1 and 2 myocardial infarction

(p=0.25) or type 2 myocardial infarction and myocardial injury (p=0.42).

Among patients with type 2 myocardial infarction, predictors of mortality at 2-

years included age (HR 1.04, 95% CI: 1.01-1.078, p=0.004), congestive heart failure

(HR 3.32, 95% CI: 1.49-7.41, p=0.003) and beta-blockers (HR 0.334, 95% CI: 0.15-

0.73, p=0.006) (Figure 4, Supplemental Table 9). For myocardial injury, predictors of

mortality at 2-years included: age (HR 1.034, 95% CI: 1.02-1.06, p<0.0001), maximum

cTnI (HR 1.74, 95% CI 1.18-2.55, p=0.005), congestive heart failure (HR 2.04, 95% CI:

1.19-3.51, p=0.01), and ACEI (HR 0.42, 95% CI 0.23-0.78, p=0.006) (Figure 5,

Supplemental Table 9).

Incidence using contemporary vs. high-sensitivity cTnI assays

The incidence of patients with 1 cTnI >99th percentile, type 1 myocardial infarction,

type 2 myocardial infarction and myocardial injury using a contemporary vs. hs-cTnI

assay is shown in Figure 6 (Supplemental Table 10). Concordance between the

contemporary and hs-cTnI assays is shown in Table 2. Discordant diagnoses were due

to either a) a different test result, in which case most were classified as myocardial

injury with either assay; or b) differences in adjudication, in which case most were

between type 2 myocardial infarction and myocardial injury.

30% of patients had 1 cTnI >99th percentile using contemporary cTnI, while 26%

had 1 hs-cTnI >99th percentile (p=0.003). Similarly, relative to contemporary cTnI, a

lower incidence of acute myocardial infarction was observed using hs-cTnI (10.8% vs.

13.2%, p=0.032). A lower rate of acute myocardial infarction was seen in men (cTnI

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13.7% vs. hs-cTnI 9.8%, p=0.009), with no difference observed in women (cTnI 12.6%

vs. hs-cTnI 12.0%, p=0.75).

The incidence of type 1 myocardial infarction did not change between assays

(cTnI 4.7% vs. hs-cTnI 4.5%, p=0.8). No differences were observed in type 1 myocardial

infarction rates for both men (cTnI 5.0% vs. hs-cTnI 4.5%, p=0.58) and women (cTnI

4.3% vs. hs-cTnI 4.6%, p=0.79). The incidence of type 2 myocardial infarction

decreased using hs-cTnI (8.5% vs. 6.3%, p=0.01), with a reduction seen in men (cTnI

8.7% vs. hs-cTnI 5.3%, p=0.0047) and no difference seen in women (cTnI 8.3% vs. hs-

cTnI 7.5%, p=0.56).

The rate of myocardial injury was similar using either assay (cTnI 17% vs. hs-

cTnI 15%, p=0.1). For men, compared to cTnI, a lower rate of myocardial injury was

seen using hs-cTnI (18.3% vs. 12.4%, p=0.0005), whereas for women, no difference

was observed (15.5% vs. 18.1%, p=0.18).

DISCUSSION

Our study provides several unique observations. First, we demonstrate that type 2

myocardial infarction occurs frequently in clinical practice with an incidence of 8.5%,

corresponding to 28% of cTnI increases or 65% of myocardial infarctions, and

associated with poor short- and long-term outcomes. Moreover, compared to patients

without myonecrosis, patients with type 2 myocardial infarction have significantly higher

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mortality and post discharge major adverse cardiac events rates within 180-days, with

mortality rates >20% at 2-years.

Studies assessing the incidence of type 2 myocardial infarction have shown a

wide range in frequency7. Contrary to studies performed outside the United States (US)

or assessing more select populations, our findings are aligned with the results of our

DIAMOND-T (Diagnostic Improved Accuracy for Myocardial infarction with Delta

Troponin) study5, in which type 2 myocardial infarction represented almost three-

quarters of myocardial infarctions, as well those observed by Meigher et al. who

reported that 35% of cTnI increases or 57% of all myocardial infarctions were due type

2 myocardial infarction13. Similarly, in CASABLANCA (Catheter Sampled Blood Archive

in Cardiovascular Diseases)14, a study involving 1,251 patients, 73.8% of all myocardial

infarctions on follow-up had at least one type 2 myocardial infarction. These

observations emphasize that while studies performed outside the US often report lower

incidence rates4,6, studies in the US have higher rates of type 2 myocardial infarction.

In regards to prognosis, our study complements observations that we and others

have made in recent years demonstrating that compared to patients without myocardial

necrosis, patients with type 2 myocardial infarction have worse outcomes, independent

of covariates4,5,15,16. Despite being frequent and associated with poor outcomes, no

guidelines exist addressing the diagnosis and management of type 2 myocardial

infarction7,9. Conversely, patients with type 1 myocardial infarction benefit from robust,

protocolized, clinical-practice guidelines, and evidence geared towards the

management of atherothrombosis17. Our study highlights these differences, with

patients having type 2 myocardial infarction being less likely to be evaluated by

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cardiology consultants, as well as less likely to undergo additional studies compared to

type 1 myocardial infarction. Further, our study informs about predictors of long-term

mortality, including beta-blockers, which were shown to be associated with a decreased

likelihood of mortality at 2-years.

Second, using either the contemporary or high-sensitivity assay, we have shown

that myocardial injury is the predominant cause of myocardial necrosis in contemporary

practice, with only 15% of cTnI increases being due to due to type 1 myocardial

infarction. Despite the absence of overt myocardial ischemia, however, we demonstrate

that patients with myocardial injury also have poor short- and long-term outcomes.

Compared to patients without myonecrosis, patients with myocardial injury had higher

rates of all-cause mortality and post-discharge major adverse cardiac events at 180-

days. Our findings are consistent with recent studies3,4,16 and demonstrate that patients

with myocardial injury are at high-risk, independent of covariates, and have mortality

rates comparable to type 2 myocardial infarction. These patients have numerous

etiologies leading to myocardial injury; with the most common causes in the current

study being renal failure, congestive heart failure and neurological conditions. These

observations underscore how the presence of cTnI concentrations >99 th percentile do

not equate myocardial infarction, but more likely myocardial injury.

Lastly, contrary to the perception that the adoption of hs-cTn assays will

uniformly be associated with more myocardial injury and infarction, we have shown that

the number of patients with concentrations >99th percentile, as well as the incidence of

acute myocardial infarction is actually significantly lower using hs-cTnI. These results

are of unique importance, particularly in the US, where hs-cTn assays have not been

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yet implemented into clinical practice and concern exists about adopting hs-assays due

to an expected increase in myocardial injury and infarction. Our findings, based Abbott

Diagnostics assays studied, suggests these concerns are unwarranted. From an

analytical perspective, our results are supported by our recent analytical studies

showing that compared to contemporary cTnI assay, the hs-cTnI assay has a) improved

analytical imprecision at the 99th percentile and b) improved analytical sensitivity

demonstrated by ability to measure more concentrations within the normal range

without an overall increase in the number of concentrations >99th percentile10,12. Further,

our results underscore how the local contemporary assay used before transitioning to a

hs-assay will influence the impact upon adoption.

Our study has limitations. First, our findings related to the benefit of beta-blockers

are hypothesis-generating. Second, debate exists surrounding how to define both type 2

myocardial infarction and myocardial injury, with further guidance expected in the Fourth

Universal Definition of Myocardial Infarction. Our study illustrates the need for guidance

and potential for misclassification, based on results showing that discordant diagnoses

due to differences in adjudication were primarily between type 2 myocardial infarction

and myocardial injury. Third, the number of events at 180-days limited our analytical

power. Lastly, studies comparing other assays are needed.

CONCLUSIONS

Using a contemporary cTnI or hs-cTnI assay, concentrations >99th percentile are

encountered in approximately a third of patients, the majority being secondary to non-

atherothrombotic conditions. Compared to patients without myonecrosis, patients with

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type 2 myocardial infarction and myocardial injury worse short-term outcomes, with

mortality rates >20% at 2 years. Further, the use of hs-cTnI does lead to more acute

myocardial injury or infarction.

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13. Meigher S, Thode HC, Peacock WF, Bock JL, Gruberg L, Singer AJ. Causes of

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14. Gaggin HK, Liu Y, Lyass A, van Kimmenade RR, Motiwala SR, Kelly NP, Mallick

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Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014; 64 (24):

e139-228.

Figure 1. 180-day all-cause mortality and post discharge major adverse cardiac events

comparing patients without myonecrosis to type 1 myocardial infarction, type 2

myocardial infarction and myocardial injury.

Figure 2. 180-day Kaplan-Meier survival curve for patients without myonecrosis (no

myocardial infarction with cTnI <99th percentile), type 1 myocardial infarction, type 2

myocardial infarction and myocardial injury.

Figure 3. 2-year Kaplan-Meier survival curve for type 1 myocardial infarction, type 2

myocardial infarction and myocardial injury.

Figure 4. Predictors of long-term mortality for type 2 myocardial infarction.

Figure 5. Predictors of long-term mortality for myocardial injury.

Figure 6. Incidence of myocardial necrosis (1 cTnI >99th percentile), acute myocardial

infarction, type 1 myocardial infarction, type 2 myocardial infarction and myocardial

injury using a contemporary vs. hs-cTnI assay.

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Table 1. Baseline characteristics for patients with type 1 myocardial infarction, type 2

myocardial infarction and myocardial injury.

Type 1 Type 2 Myocardial P value P value P value


all Type 1 Type 2
myocardial myocardial injury
vs. type vs.
infarction infarction N=280
2 injury
N=77 N=140
Demographics
Age (years) mean (SD) 61 (14) 60 (15) 62 (15) 0.52 0.74 0.27
Women n (%) 31 (40) 60 (43) 112 (40) 0.85 0.71 0.57
Medical history
Hypertension n (%) 62 (81) 104 (74) 214 (76) 0.58 0.30 0.63
Diabetes mellitus n (%) 32 (42) 43 (31) 107 (38) 0.20 0.11 0.13
Dyslipidemia n (%) 50 (65) 61 (44) 137 (49) 0.01 0.003 0.30
Coronary artery disease n 24 (31) 24 (17) 65 (23) 0.06 0.02 0.15
(%)
Prior myocardial infarction 19 (25) 15 (11) 41 (15) 0.02 0.007 0.26
n (%)
Prior percutaneous coronary 19 (25) 12 (9) 32 (11) 0.002 0.001 0.37
intervention n (%)
Prior coronary artery bypass 4 (5) 5 (4) 27 (10) 0.06 0.57 0.03
graft n (%)
Congestive heart failure n 10 (13) 40 (29) 84 (30) 0.01 0.01 0.76
(%)
Atrial fibrillation n (%) 7 (9) 16 (11) 35 (13) 0.71 0.59 0.75
Peripheral vascular disease 5 (6) 3 (2) 8 (3) 0.19 0.10 0.67
n (%)
Cerebrovascular disease n 3 (4) 18 (13) 40 (14) 0.05 0.03 0.69
(%)
Renal insufficiency, non- 13 (17) 20 (14) 53 (19) 0.49 0.61 0.24
dialysis n (%)
End-stage renal disease on 2 (3) 12 (9) 42 (15) 0.005 0.09 0.06
hemodialysis n (%)
History of cocaine or 6 (8) 28 (20) 31 (11) 0.01 0.02 0.01
methamphetamine use

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and/or other stimulant use
n (%)
History of tobacco use n 23 (30) 52 (37) 85 (30) 0.33 0.28 0.16
(%)
Presenting symptom
Chest discomfort n (%) 38 (49) 22 (16) 41 (15) <0.0001 <0.0001 0.77
Dyspnea n (%) 40 (52) 72 (51) 98 (35) 0.001 0.94 0.001
Arm and/or shoulder 30 (39) 15 (11) 18 (6) <0.0001 <0.0001 0.12
discomfort n (%)
Jaw and/or neck discomfort 12 (16) 6 (4) 9 (3) <0.0001 0.004 0.58
n (%)
Epigastric discomfort n (%) 8 (10) 8 (6) 14 (5) 0.21 0.21 0.76
Nausea and/or vomiting n 25 (33) 25 (18) 46 (16) 0.006 0.01 0.71
(%)
Fatigue n (%) 5 (7) 5 (4) 14 (5) 0.62 0.33 0.51
Diaphoresis n (%) 16 (21) 16 (11) 17 (6) 0.0005 0.06 0.05
Vitals signs
Body mass index (BMI) 31 (8) 29 (8) 30 (9) 0.20 0.05 0.32
mean (SD)
Heart rate (beats per minute) 85 (19) 100 (30) 90 (24) <0.0001 <0.0001 0.0002
mean (SD)
Temperate (C) mean (SD) 36.5 (0.7) 36.6 (0.9) 36.7 (1.5) 0.64 0.57 0.59
Systolic blood pressure 153 (27) 154 (39) 144 (33) 0.005 0.89 0.005
(mmHg) mean (SD)
Diastolic blood pressure 86 (19) 92 (27) 82 (23) 0.0003 0.06 <0.0001
(mmHg) mean (SD)
Pulse oximetry mean (SD) 95 (10) 94 (9) 95 (9) 0.032 0.51 0.13
Laboratory measurements, biochemistry
Baseline sensitive 1.8 (6.6) 0.07 (0.1) 0.1 (0.2) <0.0001 0.003 0.21
contemporary cTnI
concentration (g/L) mean
(SD) (n=497)
Baseline sensitive 1.4 (5.9) 0.07 (0.1) 0.1 (0.2) <0.0001 0.007 0.11
contemporary cTnI
concentration (g/L),
excluding STEMIs mean

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(SD) (n=490)
Maximum sensitive 9.9 (18) 0.6 (2.0) 0.2 (0.4) <0.0001 <0.0001 0.001
contemporary cTnI
concentration (g/L) mean
(SD) (n=497)
Maximum sensitive 7.5 (15.1) 0.6 (2.1) 0.2 (0.4) <0.0001 <0.0001 0.001
contemporary cTnI
concentration (g/L),
excluding STEMIs mean
(SD) (n=490)
Creatinine (mg/dL) mean 1.4 (1.5) 2.2 (3.6) 3.2 (7.3) 0.04 0.08 0.12
(SD) (n=477)
Estimated glomerular 83 (44) 73 (49) 62 (43) 0.001 0.15 0.02
-1
filtration rate, mL min (1.73
2 -1
m) mean (SD) (n=488)
Blood urea nitrogen (mg/dL) 19.6 (16) 28.3 (26) 30.4 (27) 0.01 0.01 0.45
(n=***)
Hemoglobin (g/dL) mean 13.3 (2) 12.8 (3) 12.3 (3) 0.01 0.16 0.07
(SD) (n=492)
Hematocrit (%) mean (SD) 39.7 (6) 38.7 (8) 36.7 (8) 0.002 0.30 0.01
(n=490)
NT-terminal pro-brain 3715 2974 7409 0.01 0.83 0.01
natriuretic peptide (ng/L) (4450) (3628) (12626)
mean (SD) (n=165)
Lactate (mmol/L) mean 3.2 (3.0) 4.3 (3.8) 2.9 (2.6) 0.02 0.26 0.01
(SD) (N=171)
12-lead electrocardiogram (ECG) at presentation
Adjudicated as a diagnostic 6 (8) 1 (1) 0 (0) <0.0001* 0.01* 0.33*
ECG with ischemic ST-
segment elevation changes
(STEMI) n (%)
Any ST-segment elevation 24 (31) 31 (22) 58 (21) 0.15 0.14 0.74
n (%)
ST depression and/or T wave 40 (52) 74 (53) 101(36) 0.001 0.90 0.001
changes n (%)
Pathological Q wave n (%) 15 (20) 16 (11) 50 (18) 0.17 0.10 0.09
Nonspecific ST-T wave 18 (23) 56 (40) 89 (32) 0.04 0.01 0.10

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changes n (%)
Atrial fibrillation/flutter n (%) 3 (4) 22 (16) 28 (10) 0.02 0.01 0.09
*Indicates that Fishers Exact Test was used

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Table 2. Concordance between contemporary cTnI and hs-cTnI assays for patients

without necrosis (serial serial measurements 99th percentile), type 1 myocardial

infarction (K=0.72, 95% CI 0.64-0.81, 98% concordance), type 2 myocardial infarction

(K=0.53, 95% CI 0.45-0.60, 93% concordance) and myocardial injury (K=0.58, 95% CI

0.52-0.63, 89% concordance). Boxes shaded in dark grey represent concordant

diagnoses. Boxes shaded in light grey represent discordant diagnoses triggered by a

different test result. Boxes that are not shaded (except for those representing total

results) represent discordant diagnoses due to adjudication only, not due to a different

test result.

High-sensitivity cTnI assay

Contemporary Without Type 1 Type 2 Myocardial Total

cTnI assay myonecrosis myocardial myocardial injury

infarction infarction

Without 1,104 1 4 34 1,143

myonecrosis

Type 1 10 56 2 9 77

myocardial

infarction

Type 2 31 8 68 33 140

myocardial

infarction

Myocardial 73 9 29 169 280

injury

Total 1,218 74 103 245 1,640

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