Acta Neurol Belg

DOI 10.1007/s13760-015-0596-8

ORIGINAL ARTICLE

Elevation of cardiac troponin T in patients with amyotrophic

lateral sclerosis
Lukas Mach1,2,3 Tomas Konecny1,2,4 Katerina Helanova1,2,5 Allan S. Jaffe1,6

Eric J. Sorenson7 Virend K. Somers1 Guy S. Reeder1

Received: 15 July 2015 / Accepted: 30 December 2015

Belgian Neurological Society 2016

Abstract Limited evidence suggests that specificity of
cardiac troponin T (cTnT), a highly sensitive biomarker of
myocardial injury, is reduced in patients with skeletal
myopathies. Whether amyotrophic lateral sclerosis
(ALS)the most common motor neuron diseasecould
be also associated with abnormal plasma or serum cTnT
levels remains unclear. Our objective was to assess cTnT
levels in patients with ALS without known cTnT elevating
conditions. Among ALS patients seen at our institution
until 2012 we identified those who had their cTnT mea-
sured. Patients who suffered from conditions known to
elevate cTnT were excluded. A casecontrol analysis
comparing cTnT levels of these ALS patients to matched
non-ALS controls fulfilling the same inclusion criteria was
performed. We included 40 ALS patients of whom 27
(68 %) patients had a positive cTnT. In the control group
(n = 40), 2 (5 %) tested as cTnT positive (p \ 0.001).
Among the ALS patients who underwent cTnT evaluation
on more occasions (n = 7; median follow-
up = 1.08 years), 2 (29 %) patients tested positive during
the initial measurement while 6 (86 %) of them had posi-
tive cTnT at the subsequent evaluations. ALS patients with
increased cTnT had been diagnosed with ALS significantly
earlier than those without the elevation. Our findings raise
the possibility that ALS may cause cTnT elevations. Fur-
ther studies are needed to confirm these findings, clarify the
pathophysiological mechanism, and establish the signifi-
cance of cTnT elevations in patients with ALS.
Keywords Acute coronary syndrome
Neuromuscular
disease
Amyotrophic lateral sclerosis
Troponin T
Introduction

& Tomas Konecny
tomkony@hotmail.com
1
Division of Cardiovascular Diseases, Mayo Clinic, 200 First
Street SW, Rochester, MN 55905, USA
2
International Clinical Research Center, St. Annes University
Hospital Brno, Pekarska 53, Brno 656 91, Czech Republic
3
Medical Faculty, Masaryk University, Kamenice 5,
Brno 625 00, Czech Republic
4
University of Southern California, 1975 Zonal Ave,
Los Angeles, CA 90033, USA
5
Department of Cardiology, University Hospital Brno,
Jihlavska 340/20, Brno, Czech Republic
6
Department of Laboratory Medicine and Pathology, Mayo
Clinic, 200 First Street SW, Rochester, MN 55905, USA
7
Neuromuscular Division, Department of Neurology, Mayo
Clinic, 200 First Street SW, Rochester, MN 55905, USA
Background
Cardiac troponin T (cTnT) functions as a sensitive bio-
marker of myocardial injury which is commonly employed
in the clinical evaluation of suspected acute coronary
syndromes [1]. Several non-coronary conditions associated
with cTnT elevation must be taken into account in the
diagnostic algorithm, including non-ischemic cardiomy-
opathy, renal insufficiency, arrhythmias, myocarditis,
pericarditis, pulmonary embolism, pulmonary hyperten-
sion, sepsis, acute or chronic heart failure, trauma, or
rhabdomyolysis [2]. Limited evidence suggests that
pathophysiological processes present in inflammatory
skeletal myopathies can lead to raised cTnT levels [35].
Whether amyotrophic lateral sclerosis (ALS)the most
common motor neuron diseasecould be also associated
with abnormal plasma or serum cTnT levels remains

123

unclear, yet singular cases supporting this notion have been
reported [68].
Objectives
Because the knowledge of a decreased specificity of cTnT
in ALS patients could assist in appropriate evaluation of
suspected acute coronary syndromes (ACS) in these unique
and complex patients, we set to conduct (1) a retrospective
cross-sectional analysis defining what proportion of ALS
patients tested positive for cTnT despite lacking other
conditions known to elevate cTnT, (2) a casecontrol
comparison of these ALS patients to similarly selected age
and sex matched non-ALS controls, and (3) compare the
clinical characteristics and survival of ALS patients who
tested positive for cTnT to those who tested negative.
Methods
Study design
This study was approved by the Institutional Review
Board. We reviewed the medical records of all adult
patients with ALS seen at our institution until 2012 for the
availability of cTnT measurements in the clinical and
laboratory records. The diagnosis of ALS was established
by a board certified neurologist who followed the appli-
cable El Escorial World Federation of Neurology criteria
[9, 10].
Laboratory assessment
The assessment of cTnT was performed with a Roche
Diagnostics immunoassay (Indianapolis, Indiana). In
accordance with the guidelines the cut-off value for
abnormal cTnT was set on 99th percentile of normal ref-
erence population which was 0.01 ng/mL [1, 11, 12].
Repeated measurement at 3 and 6 h was performed in most
patients, and for the purposes of our study the patients were
deemed cTnT positive if any of the levels measured above
the cut-off value. If any patient had cTnT measured at
several visits, we recorded these values and planned to
report the temporal progression of cTnT in these individ-
uals. For the purposes of the casecontrol analysis, only the
values obtained during the most recent visit were used.
Demographic, laboratory, and clinical patients character-
istics were obtained from the electronic medical records.
Exclusion criteria
Patients with clinical evidence of cTnT elevating condi-
tions including coronary artery disease with at least 50 %
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occlusion in a major coronary artery, decreased left ven-
tricular ejection fraction (\50 %), renal insufficiency
(glomerular filtration rate \60 mL/min), arrhythmias
(atrial fibrillation, supraventricular and ventricular tachy-
cardia), myocarditis, pericarditis, pulmonary embolism,
pulmonary hypertension, sepsis, acute or chronic heart
failure, implanted pacemaker or defibrillator, non-ischemic
cardiomyopathy or infiltrative heart disease, artificial
valve, or after trauma, or cardiothoracic surgery, or car-
diopulmonary resuscitation were excluded (Fig. 1) [1, 2].
However, the availability of cardiovascular data varied
markedly depending on whether the clinicians responsible
for the care of the patients ordered evaluations. All of the
included patients had 12-lead ECG performed at the time
of cTnT sampling, which was negative for ischemia, the
heart rate did not exceed 100 beats per min, and all patients
were in sinus rhythm.
Control group
The control cohort was selected from consecutive patients
without known ALS or known skeletal muscle disease who
had their cTnT testing performed at our institution between
January 1st, 2008, and February 27th, 2008, with the same
exclusion criteria applied. Control subjects were matched
to the index ALS patients in a 1:1 ratio to age (2 years)
and sex.
Statistics
Results are displayed as means standard deviations, or
counts and percentages as appropriate. Pearson Chi-square
test and Wilcoxon rank-sum test were used to compare
categorical and continuous variables across the ALS and
the control groups, and across cTnT positive and negative
groups of ALS patients. For time-to-event data Kaplan
Meier curves with log-rank test were used. p value of
\0.05 was judged as statistically significant. Results are
shown as means and standard deviations, or counts and
percentages as applicable. Analysis was performed with
JMP 9.0 and Microsoft Excel.
Results
Characteristics of study subjects
We identified 98 adult patients with confirmed diagnosis of
ALS and available cTnT measurements, of whom 58
patients were excluded because of aforementioned criteria
(Fig. 1). Remaining 40 ALS patients with mean age of
64.3 11.8 years of whom 13 (32.5 %) were women were
enrolled. The earliest available cTnT measurement was
Acta Neurol Belg

Fig. 1 Flow diagram illustrates how patients were included in the CKD chronic kidney disease, LVEF left ventricular ejection fraction,
study, and lists the potentially cTnT elevating conditions which lead PE pulmonary embolism, HFNEF heart failure with normal ejection
to exclusion of part of the ALS patients. CAD coronary artery disease, fraction

from 2001. The clinical characteristics are summarized in

Table 1 which also includes the control cohort of consec-
utive 40 non-ALS patients fulfilling the same exclusion
criteria and matched to the ALS group by age and sex.

Main results

In the ALS cohort, 27 (67.5 %) patients tested positive for

cTnT, and in the control group 2 (5.0 %) patients had the
cTnT result above the cut-off value (p \ 0.001) (Fig. 2).
The elevations of cTnT were generally modest with mean
value of 0.05 0.07 ng/mL. The clinical context of the
cTnT assessments in these ALS patients is specified in
Table 2, along with the results of their 3 and 6 h cTnT
assessment where available. The most common presenta- Fig. 2 The proportion of cTnT positive patientscomparison of
tions which lead to cTnT testing in the control cohort were ALS patients and controls
chest pain (20 patients, 50.0 %), syncope (3 patients,
7.5 %), hematology evaluation (3 patients, 7.5 %), and was likely due to negative cTnT tests in most of these
postoperative follow-up (3 patients, 7.5 %). Availability of patients. None of the controls had coronary angiography
cardiovascular data was low in this control cohort which result available, 14 had echocardiography performed, and

Table 1 Patient characteristics

ALS (n = 40) Non-ALS (n = 40) p value

Positive cTnT 27 (67.50 %) 2 (5.00 %) \0.0001

Age (years) 64.30 (11.82) 64.13 (11.82) 0.95
Sex (female) 13 (32.50 %) 13 (32.50 %) 1
Body mass index (kg/m2) 27.11 (6.46) 28.23 (4.45) 0.40
Hypertension 14 (35.00 %) 13 (37.14 %) 1
Hyperlipidemia 11 (27.50 %) 8 (22.86 %) 0.79
Diabetes mellitus 3 (7.69 %) 1 (2.86 %) 0.62

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 Table 2 Results of cTnT measured in ALS patients in the context of clinical evaluation
Patient Age Sex Clinical context cTnT (ng/mL) Mean cTnT CK CK-MB Creatinine Echo Coronary Degree of respiratory
number (years) (ng/mL) (U/L) (ng/mL (mg/dL) angiogram impairment

123
Initial 3h 6h

1 76 F Dyspnea 0.01 0.03 0.077 0.081 Normal NP 1

2 86 M Dyspnea 0.02 0.02 0.02 0.015 0.009 0.8 Normal NP 3
3 61 F Chest pain 0.09 0.17 0.14 0.056 0.047 0.4 Normal NP 4
4 52 M Dyspnea 0.06 0.047 0.026 11.3 0.3 Normal No occlusions 2
5 76 M Dyspnea 0.08 0.067 0.011 183 9.3 0.6 Normal NP 2
6 75 F Abdominal pain 0.18 0.090 0.090 3.3 1.1 Normal NP 4
7 83 F Cough 0.01 0.005 0.005 NP NP 1
8 64 F Dysphagia \0.01 0.6 Normal NP 1
9 79 M Chest discomfort 0.03 0.03 0.03 0.03 0 1.1 Normal NP 1
10 37 M Dyspnea 0.34 908 55.2 Normal No occlusions 2
11 46 M Chest pain 0.05 0.04 0.06 0.05 0.008 0.7 NP NP 0
12 71 M Dyspnea 0.21 NP NP 1
13 73 M Monitoring after PEG \0.01 0.02 0.01 0.01 0.008 0.6 NP NP 2
14 72 M Dysphagia 0.04 7.2 Normal NP 1
15 54 M Dyspnea 0.21 0.255 0.045 6.8 0.4 NP NP 4
16 68 M Abdominal pain 0.02 0.03 0.04 0.03 0.01 0.6 Normal Stenosis \ 50 % 1
17 38 M Dyspnea 0.02 0.02 0.02 0 0.5 NP NP 1
18 53 M Dyspnea 0.15 0.16 0.13 0.147 0.013 0.1 NP NP 2
19 68 M Weakness 0.08 41 7.2 1 NP NP 1
20 67 M Dyspnea 0.05 5.5 Normal NP 1
21 83 M Dyspnea 0.04 0.05 0.05 0.047 0.005 0.6 Normal No occlusions 2
22 47 M Monitoring after cervical 0.03 0.03 0.03 0.03 0.2 NP NP NA
foraminotomy
23 74 M Dyspnea \0.01 0 111 0.9 NP NP NA
24 61 F Weakness \0.01 0 0.8 Normal NP 1
25 73 F Altered mental status 0.02 0.02 0.7 NP NP NA
26 69 M Dyspnea 0.1 0.1 0.7 Normal NP 1
27 60 F Dyspnea \0.01 \0.01 \0.01 0 0.4 Normal NP 1
28 54 M Dyspnea \0.01 0 198 4.9 0.6 NP NP 2
29 62 F Weakness \0.01 0 50 0.8 NP NP 1
30 63 M Chest pain \0.01 0 Normal NP 2
31 54 M Dyspnea \0.01 0 1.3 0.7 NP NP 4
32 69 M Syncope \0.01 0 1.1 NP NP 3
33 70 M Dyspnea 0.01 0.01 0.8 NP NP 1
34 59 F Dyspnea 0.03 0.03 8.7 0.7 Normal NP 2
Acta Neurol Belg
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Degree of respiratory impairment: 0 = without manifestation of respiratory dysfunction, 1 = impaired tolerance of physical exercise, 2 = use of non-invasive respiratory support at night,
3 = chair bound, 4 = ventilator dependent. Normal echocardiogram defined as: left ventricular ejection fraction [50 %, and absence of significant valve pathology, ventricular/atrial
all had normal ECG findings (as defined above). The two
Degree of respiratory patients with positive cTnT tests did not show rising pat-
tern of cTnT values and their electrocardiographic, and
echocardiographic findings were negative for ischemia
impairment

(absence of regional wall motion abnormalities).

Among the 40 ALS patients, 13 completed the full set of
1
1
1
1
1
2
cTnT tests (initial, 3rd and 6th hour) and 2 patients had two
out of the three assessments. A rising pattern of values was
observed in patients #3, #13, #16, #40, while in the other
angiogram
Coronary

cases the values remained stable. The measurement of

other cardiac biomarkers was not consistently performed at
NP
NP
NP
NP
NP
NP

our institution, nevertheless, the available values of crea-

tinine kinase and the MB fraction of creatinine kinase at
Normal
Echo

the time of cTnT measurement where available are shown

NP
NP

NP
NP
NP

in Table 2.
Creatinine

Chronic progression of cTnT levels

(mg/dL)

0.9
0.7
0.5
0.6

Seven ALS patients had their plasma cTnT assessed on 2

or more visits with median length of follow-up 1.08 years
CK-MB

(25 and 75th quartile: 0.82, 1.81). While 2 (29 %) of the

(ng/mL

patients tested positive on the initial cTnT measurement,

there were 6 (86 %) with positive cTnT at the last available
follow-up (Fig. 3).
(U/L)

68
CK

Features of cTnT positive/negative ALS patients

0.005 0.008
Mean cTnT

Table 3 includes the clinical characteristics of ALS

(ng/mL)

patients who tested positive for cTnT as opposed to those

0.03

who did not have their cTnT values elevated. Those with
0
0
0
0

NP not performed, NA not applicable, PEG percutaneous endoscopic gastrostomy

increased cTnT had been diagnosed with ALS significantly

\0.01
\0.01 \0.01 \0.01
\0.01 \0.01 \0.01
\0.01 \0.01 \0.01

0.02
6h

earlier than those without the elevation (22.9 18.5 vs.

11.9 12.2 months; p = 0.032). Time of survival from
cTnT (ng/mL)

0.01

ALS diagnosis and from cTnT sampling was analyzed in

3h

ALS patients where the mortality data were available

hypertrophy or dilatation, and regional wall motion abnormality.
\0.01

0.03
\0.01
Initial

(n = 27) (Fig. 4).

cTnT values in bold are those above the given cut-off.
Hypercapnia, hypotension

Discussion

Novel findings
Clinical context

Chest pain
Chest pain
Weakness

The novel findings of this study are: (1) abnormal eleva-

Dyspnea
Dyspnea

tions of cTnT are present in a substantial proportion of

ALS patients who underwent clinical measurement of
cTnT, but lacked other clinically overt conditions respon-
Sex

M
M

M
F

F
F

sible for elevated and/or increasing the cTnT values, (2)

the proportion of cTnT positive ALS patients is signifi-
(years)
Table 2 continued
Age

cantly greater than in age and sex matched controls without

72
70
48
64
67
54

known ALS or known skeletal muscle disease, (3) the

cTnT levels chronically increased in most ALS patients
number
Patient

who had a repeated measurement at a subsequent visit, and

35
36
37
38
39
40

(4) cTnT elevations seemed to occur later in the course of

123

this progressive disease. Although no statistically signifi-
cant difference in survival was observed, ALS patients with
elevated cTnT showed trend towards earlier mortality.
Clinical relevance
Our findings suggest that cTnT elevations are prevalent in
ALS patients. Additional studies are needed to confirm
these findings, and to possibly refine the diagnostic algo-
rithm applied to ALS patients with suspected ACS so that
the risk of under-diagnosis of coronary disease is balanced
with preventing potentially unnecessary therapeutic inter-
ventions (including the adverse risk of long term dual anti-
platelet use in often respirator dependent patients) [13, 14].
Whether raised levels of cTnT could predict clinical out-
comes in ALS should also be addressed in future studies.
Temporal kinetics of cTnT
The small number of patients who had cTnT checked at
several temporally separated visits does not allow us to
draw conclusions about temporal kinetics of cTnT, but we
note the trend for increased prevalence of abnormal cTnT
with progression of ALS symptomatology. A prospective
study would be needed to confirm this important finding.
The fact that patients with elevated cTnT had had the
diagnosis of ALS for significantly longer also supports the
notion that cTnT levels could potentially correlate with
disease progression. The short term (3 and 6 h) kinetics did
not in most cases show dynamic patterns which may be
helpful in differentiating the elevations from those seen in
ACS.
Fig. 3 Long-term progression
of cTnT in ALS patients. ALS
patients without other known
causes for cTnT elevation who
had their cTnT assessed on
more than one visit (n = 7).
Median follow-up time was
1.08 years (25 and 75th quartile:
0.82, 1.81). The number of each
patient refers to the
corresponding patient identifier
in Table 2
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Cause of cTnT elevation
This study cannot elucidate the exact mechanism of where
the cTnT which seems to be commonly present in the
serum of ALS patients originates from. Despite the lack of
clinically overt ischemic cardiomyopathy (normal ECG,
echocardiographic evaluation, symptomatic manifestation,
stress testing), the paucity of angiographic evidence in
many of the ALS patients precludes the exclusion of
coronary stenosis as the culprit leading to the cTnT ele-
vation. Alternative hypotheses could include the possibility
that cTnT originates from the atrophic skeletal muscles via
re-expression similarly to how cardiac isoform of troponin
T is produced in the atrophying skeletal muscles of patients
with immune-mediated skeletal myopathies [15]. Data
from sizeable studies suggest that cTnT elevations are
common in inflammatory myopathies, and a study using
skeletal muscle biopsy proved presence of this isoform in
diseased skeletal muscles [5, 15]. Should plausibility of
this mechanism be proved by skeletal muscle biopsy in
ALS, the disease could list among the rare conditions in
which cTnT may originate from tissues other than myo-
cardium. Additional mechanisms of myocardial injury
which could lead to abnormal cTnT include hypoxia sec-
ondary to progressive respiratory failure [6], or derange-
ment of autonomic innervation of the heart known to exist
in ALS patients [16, 17]. Whether myocardial pathology
could be caused by mechanisms specific to ALS has not
been clearly elucidated. Further investigation of all of the
mentioned mechanisms could provide interesting insight
into the pathophysiology of ALS and its progression.
Acta Neurol Belg

Table 3 Comparison of cTnT positive and negative ALS patients

cTnT positive ALS cTnT negative ALS p value
patients (n = 27) patients (n = 13)

Age (years) 65.1 13.4 62.7 7.6 0.48

Sex (female) 7 (25.9 %) 6 (46.2 %) 0.2
Degree of respiratory distress
Without manifestation of respiratory dysfunction 1 (4 %) 0
Impaired tolerance of physical exercise 12 (48 %) 8 (66.7 %)
Use of non-invasive respiratory support at night 8 (32 %) 2 (16.7 %)
Chair bound 1 (4 %) 1 (8.3 %)
Ventilator dependent 3 (12 %) 1 (8.3 %)
Duration of ALS at the time of cTnT sampling (months) 22.9 18.5 11.9 12.2 0.032
Survival from ALS diagnosis (months) 26.0 18.8 33.3 32.1 0.58
Survival from cTnT sampling (months) 5.7 6.1 20.3 31.3 0.26

Limitations

Despite the inherent limitations, this pilot retrospective

study represents the largest to date evaluation of cTnT in
ALS patients, and its hypothesis forming potential is
increased by the fact that it concurs with previously pub-
lished case reports [68]. All of the cTnT evaluations in
this study were clinically indicated as were evaluations for
the etiology of any given elevations. This might have
introduced selection bias into this study, however, this was
true for both the ALS and for the control group. It might
also have led to a lack of information about the presence of
concurrent cardiac disease. Given the rarity of ALS in
general population, and the fact that this disease commonly
progresses relatively rapidly to lethal consequences, we
needed to include patients evaluated at different times over
a period of 11 years, but all these patients were evaluated
at a single center with significant experience both in the
laboratory evaluation of cTnT and in the specialized care
for ALS patients. Given the retrospective nature of this
study, we were unable to rule out ischemic myocardial
injury by angiography in many of the ALS patients, but
even a prospective study would be ethically limited in this
regard. Additional limitation lies in the lack of more
detailed pathological investigation as well as insufficient
information about other cardiac biomarkers such as cardiac
troponin I, CK, or CK-MB [7, 18].

Fig. 4 Survival of ALS patients. KaplanMeier curves comparing

survival from diagnosis of ALS or from cTnT sampling in cTnT
positive (solid line) and cTnT negative patients (dotted line). No
statistically significant difference was observed. Note that mortality
data were available only in 27 ALS patients
Conclusions
This study raises the possibility that ALS patients may
commonly present with false positive cTnT results more
commonly than non-ALS patients, and additional studies

123

are needed to elucidate the exact pathophysiologic mech-
anisms responsible for such cTnT elevations. Chronic
increase of cTnT in ALS patients could parallel the
symptomatic progression of their disease.
Acknowledgments This study was supported by the Mayo Foun-
dation for Education and Research, European Regional Development
FundProject FNUSA-ICRC (CZ.1.05/1.1.00/02.0123), and the
European Social Fund within the Project Young Talent Incubator
(CZ.1.07/2.3.00/20.0022).
Compliance with ethical standards
Conflict of interest Dr. Allan S. Jaffe has or presently consults for
most of the major diagnostic companies. The other authors have no
conflicts of interest to disclose.
Ethical standards All procedures performed in this study involving
human participants were in accordance with the ethical standards of
the institutional research committee and with the 1964 Helsinki
declaration and its later amendments or comparable ethical standards.
Informed consent For this type of study formal consent is not
required.
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