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Use of a highly-sensitive cardiac troponin I assay in a screening population for
hypertrophic cardiomyopathy: a case-referent study
BMC Cardiovascular Disorders 2013, 13:70 doi:10.1186/1471-2261-13-70
Catherine M McGorrian ([email protected])
Sarah Lyster ([email protected])
Andrew Roy ([email protected])
Heloise Tarrant ([email protected])
Mary Codd ([email protected])
Peter Doran ([email protected])
Maria Fitzgibbon ([email protected])
Joseph Galvin ([email protected])
Niall G Mahon ([email protected])
ISSN 1471-2261
Article type Research article
Submission date 5 February 2013
Acceptance date 14 August 2013
Publication date 11 September 2013
Article URL http://www.biomedcentral.com/1471-2261/13/70
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BMC Cardiovascular Disorders
2013 McGorrian et al.
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Use of a highly-sensitive cardiac troponin I assay in
a screening population for hypertrophic
cardiomyopathy: a case-referent study
Catherine M McGorrian
1,2,*

Email: [email protected]
Sarah Lyster
3

Email: [email protected]
Andrew Roy
1

Email: [email protected]
Heloise Tarrant
4

Email: [email protected]
Mary Codd
2

Email: [email protected]
Peter Doran
5

Email: [email protected]
Maria Fitzgibbon
4

Email: [email protected]
Joseph Galvin
1,6

Email: [email protected]
Niall G Mahon
1

Email: [email protected]
1
Department of Cardiology, Mater Misericordiae University Hospital, Eccles St.,
Dublin 7, Ireland
2
UCD School of Public Health, Physiotherapy and Population Science, UCD
Belfield, Dublin 4, Ireland
3
UCD School of Biomolecular and Biomedical Science, UCD, Belfield, Dublin
4, Ireland
4
Department of Clinical Biochemistry, Mater Misericordiae University Hospital,
Eccles St., Dublin 7, Ireland
5
Clinical Research Centre, Mater Misericordiae University Hospital, Eccles St.,
Dublin, 7, Ireland
6
Department of Cardiology, Connolly Hospital Blanchardstown, Dublin 15,
Ireland
*
Corresponding author. Department of Cardiology, Mater Misericordiae
University Hospital, Eccles St., Dublin 7, Ireland
Abstract
Background
Hypertrophic cardiomyopathy (HCM) is a genetic condition, and relatives of affected persons
may be at risk. Cardiac troponin biomarkers have previously been shown to be elevated in
HCM. This study examines the new highly-sensitive cardiac troponin I (hsTnI) assay in a
HCM screening population.
Methods
Nested casecontrol study of consecutive HCM sufferers and their relatives recruited from
May 2010 to September 2011. After informed consent, participants provided venous blood
samples and clinical and echocardiographic features were recorded. Associations between the
natural log (ln) of the contemporary troponin I (cTnI) and hsTnI assays and markers of
cardiac hypertrophy were examined. Multiple regression models were fitted to examine the
predictive ability of hsTnI for borderline or definite HCM.
Results
Of 107 patients, 24 had borderline and 19 had definite changes of HCM. Both TnI assays
showed significant, positive correlations with measures of cardiac muscle mass. After age
and sex adjustment, the area under the receiver operator characteristic (AUROC) curve for
the outcome of HCM was 0.78, 95% CI [0.65, 0.90], for ln(hsTnI), and 0.66, 95% CI [0.51,
0.82], for ln(cTnI) (p=0.11). Including the hsTnI assay in a multiple-adjusted screening
model for HCM resulted in a non-significant improvement in both the AUROC and
integrated discrimination index.
Conclusions
Both cTnI and hsTnI show a graded, positive association with measures of cardiac muscle
mass in persons at risk of HCM. Further studies will be required to evaluate the utility of
these assays in ECG- and symptom-based identification of HCM in at-risk families.
Keywords
Hypertrophic cardiomyopathy, High-risk screening, Troponin I, Biomarkers, Highly-sensitive
assays
Background
Hypertrophic cardiomyopathy (HCM) is a genetic condition with otherwise unexplained left
ventricular hypertrophy in the absence of LV chamber dilatation [1]. It is a relatively
common condition [2], and carries an increased risk of arrhythmia and sudden cardiac death,
even in those persons with clinically silent or unrecognised HCM. Therefore, cardiac
screening of first-degree relatives of HCM probands is now advised [3]. Cascade screening
may be clinical with an electrocardiogram (ECG) and transthoracic echocardiogram (echo),
genetic (if the family mutation is identified ), or a combination of both. However, such
screening presents multiple challenges. For genetic evaluation, causative gene identification
is currently possible in 40-70% of tested families [4]. In clinical evaluations, it can be a
challenge to differentiate between early HCM changes and other findings such as the
athletes heart [5] and hypertensive heart disease [6].
Biomarkers are naturally occuring molecules which may indicate a disease process. Cardiac
troponins are biomarkers which are released due to myocyte necrosis, and cardiac troponin I
(TnI) is specific to cardiac muscle. There is a known association between cardiac troponin
levels and cardiac muscle hypertrophy [7-9]. Recently, high-sensitivity cardiac troponin I (hs
cTnI) assays have become available [10], and will ultimately replace contemporary cTnI
assays. Such hsTnI assays not only provide greater precision at the 99th percentile limits, but
can also detect lower levels of troponin leak with greater sensitivity. It is not known how
hsTnI assays may behave in persons with or at risk of HCM, but it may be that these lower
levels of cTnI may provide useful screening information in such persons.
In this study, we aimed to examine the distribution of TnI, measured with both a standard
contemporary (cTnI) and new highly-sensitive assay, in a high-risk population for HCM. A
proof of concept investigation was undertaken to examine the association of cTnI and
hsTnI with echocardiographic markers of HCM, and the incremental screening value of
adding highly-sensitive biomarker data to ECG and clinical data was assessed.
Methods
Study population
The Family Heart Screening Study is a prospective single-centre cohort study of patients at
risk of familial cardiac conditions, based in a screening clinic for familial cardiomyopathies
and channelopathies. From March 2010 to August 2011, all patients attending for HCM
screening were considered for study inclusion. Patients were included if they had a first or
second degree relative with HCM, and were aged 18 and over. Only patients who provided
informed consent for both data collection and serum sampling were included in this analysis.
Ethical approval for this study was granted by the Mater Misericordiae University Hospital
Research Ethics Committee, and the study was conducted with due regard to the principles of
the Declaration of Helsinki..
Patients underwent protocol-driven clinical screening, with clinical history-taking and
examination, pedigree analysis, and ECG and echo. Data were collected on baseline
symptoms including chest pain, dyspnoea, palpitations and syncope. Patients were deemed to
be symptomatic if they described any of these symptoms. ECGs were defined as abnormal if
any typical Group 2 ECG changes were noted (i.e. presence of ST depression or T-wave
inversion, pathological Q waves, interventricular conduction delays, deviations in cardiac
axis, long or short QT and /or Brugada-like repolarisation changes) [11]. Body surface area
(BSA) was calculated for all persons in whom weight and height were available.
Echocardiograph measurements
Transthoracic echo studies were performed by a senior echocardiographer using a
commercially available system (Vivid 7, GE Healthcare, Horten, Norway) with a 3.5-MHz
transducer. Images were obtained in standard views and were digitally stored for offline
analysis (Echopac Version 7.0., GE Healthcare). The ejection fraction (EF) was calculated
using Simpsons rule [12]. Peak E and A velocities, E/A ratio and deceleration time (DT)
were recorded using pulse wave (PW) Doppler in the apical 4-chamber view. Tissue Doppler
PW analysis was also used to measure mitral annular velocities, with the sample volume at
the septal and lateral annulus insertion of the mitral valve leaflets (septal and lateral S, E
and A). Left ventricular mass (LV mass) was calculated using the American Society of
Echocardiography (ASE) method [13]. All echo images were read offline by two observers
blinded to patient history.
The interventricular septum diameter in diastole (IVSd) and left ventricular posterior wall
diameter in diastole (LVPWd) were used to calculate the IVSd/LVPWd ratio. The relative
wall thickness (RWT) was calculated by dividing the IVSd/LVPWd ratio by the left
ventricular end-diastolic diameter (LVEDD) [12]. The maximal wall thickness (MWT) was
calculated from the parasternal short-axis view in 2D Mode by taking the maximal thickness
of the left ventricular wall in end diastole in any of the following segments: anterior septum,
posterior septum, posterolateral wall and anterolateral wall. The Maron-Spirito index was
calculated by taking the sum of the left ventricular (LV) maximal thickness at each of these
segments, measured both at basal (mitral valve) and mid ventricular (papillary muscle) levels
[14]. The adjusted 2D-LVHscale was calculated as described by Forissier et al., where 2D
LVH score= 18.95+ (0.12*age in years) + (2.64*male sex) + (6.41*BSA in kg/m
2
) [15]. The
echo- and tissue doppler-based risk score of Gandjbakhch et al. for HCM mutation carrier
probability was calculated using the equation p = 19.1861 + (6.195 IVS/LPW) + (22.538
RWT) + (0.5613 septal E/Ea) [16].
Biomarker analyses
A single lithium-heparin venous sample (8ml) was drawn and transferred to a refrigerator at
4C. The samples were centrifuged within 4 hours of collection, and the plasma sample was
assigned a unique identifier number and frozen directly at 80C. The hsTnI analysis was
performed using the ARCHITECT STAT High Sensitive Troponin I assay on the
ARCHITECT i1000
SR
system (Abbott Diagnostics). The concentration of the hsTnI was read
relative to a standard curve derived with calibrators of known hsTnI concentration. The cTnI
analysis was performed on samples which had undergone a single previous thaw, with an
ARCHITECT STAT Troponin-I assay, also on the ARCHITECT i1000
SR
system. The
concentration of the cTnI present was read relative to a standard curve derived with
calibrators of known cTnI concentration. Standard procedures were followed for callibration
and norms.
For this study, a population group of 109 unaffected relatives (with a normal cardiovascular
examination, ECG and echo) served to define the 99th centile for the normal population (in
this study, 24.88pg/ml). In healthy individuals, values of troponin (Tn) are low and many fall
below the detection limit of contemporary assays. Therefore the 99th centile of the healthy
population is recommended as a clinical decision cut off value. For the contemporary cTnI
assay, the assay precision is 10% total coefficient of variation (CV) for samples 0.2 ng/mL
with an analytical sensitivity of 0.01 ng/mL at the 95% confidence interval (CI). The hsTnI
assay has a 10% CV at 0.047ng/ml with a limit of detection 0.002 ng/ml. The analytical
specificity is 0.1% cross-reactivity with skeletal troponin-I and 1% with cardiac troponin-
T and troponin-C.
Statistical analysis
Patient outcomes were defined using established echo criteria for HCM (1,3). Patients with a
MWT <13mm were deemed to have no evidence of HCM, with patients with a MWT of
15mm deemed to have a definite finding of HCM. Patients with a MWT of 13-14mm were
deemed to have borderline changes. Descriptive statistics were used to describe the clinical
and echo characteristics of the screened population by screening outcome, using contingency
tables and the Pearson chi-square test to compare categorical variables and simple analysis of
variance models (ANOVA) to compare continuous variables between the three groups. The
distribution of the cTnI and hs cTnI biomarkers in the populations were examined, and a
natural log transformation was used to allow the use of parametric statistics.
Pearsons correlation coefficient was used to examine correlations between the biomarker
measures and key echo measurements, and two way scatterplots with fitted ordinary least-
squares regression lines were used. Analysis of the biomarkers proceded as suggested by
Hlatky et al. [17]. Simple logistic regression models were fitted, adjusting for age and sex,
with either cTnI or hsTnI as the independent variable, and the presence of an abnormal echo
screening evaluation as the dependent variable. Area under the receiver operator
characteristic (AUROC) curve was calculated and compared for the logistic models described
[18]. To examine the potential utility of the biomarker in a clinic or screening context, three
forward stepped logistic models were fitted, with the a possible or definite HCM finding on
echo as the dependent variable. The first simple model had age, sex and symptoms (any of
chest pain, dyspnoea, palpitations and syncope) as independent variables; the second clinic
model then included abnormal or group 2 ECG findings [11]; and the third enhanced
model included ln(hsTnI). Measurement of the model r
2
, AUROC, and integrated
discrimination index (IDI) was undertaken [19]. All analyses were performed with
Intercooled Stata 11 (StataCorp, Texas).
Results
Complete clinical data were available on 107 patients who underwent screening for HCM.
The baseline population characteristics are shown in Table 1. Eight patients were in fact the
family proband or index case, who had been referred for assessment to confirm the HCM
diagnosis. Of these probands, seven had definite and one had borderline HCM changes on
echo. Table 2 describes the echo characteristics in this population. As might be expected by
the echo-based stratificication method used, echo markers of increased left ventricular
thickness and reduced diastolic function, as well as three echo-based scores of left ventricular
hypertrophy and HCM [14-16], were observed to increase by diagnostic stratum.
Table 1 Baseline characteristics of the study population, stratified by echocardiographic criteria of HCM
1,3

Total (n = 107) Normal screening echo (n=64) Borderline HCM (n=24) Definite HCM (n=19)
Demographic data
Age in years: mean [SD] 39.30 (13.86) 35.63 [12.26] 44.92 [12.793] 44.59 [16.63] F=6.15, p=0.003
Male sex: n(%) 63 (58002E9%) 32 (50.0%) 20 (83.3%) 11 (57.9%) 2=8.01, p=0.018
BMI in kg/m
2
: mean [SD] 26.94 (3.90) 25.67 (3.90) 29.08 [3.88] 27.70 [3.07] F=5.97, p=0.004
Relationship to the family proband
Proband: n (%) 8 (7.5%) 0 (0%) 1 (4.2%) 7 (36.85%) Fishers exact p<0.005
1
st
degree relative : n (%) 82 (76.6%) 53 (82.8%) 20 (83.3%) 9 (47.4%)
2
nd
degree or higher : n (%) 17 (15.9%) 11 (17.2%) 3 (12.5%) 3 (15.8%)
Clinical History
Any symptoms: n (%) 36 (33.6%) 18 (28.1%) 8 (33.3%) 10 (52.5%) 2=3.94, p=0.139
Chest pain: n (%) 10 (9.4%) 7 (10.9%) 2 (8.3%) 1 (5.3%)
Dyspnoea: n(%) 12 (11.2%) 5 (7.8%) 3 (12.5%) 4 (21.1%) Fishers exact p=0.267
Palpitations: n(%) 17 (15.9%) 7 (10.9%) 4 (16.7%) 6 (31.6%) Fishers exact p=0.089
History of syncope: n(%) 6 (5.6%) 2 (3.1%) 2 (8.3%) 2 (10.5%) Fishers exact p=0.286
BMI Body Mass Index.
Table 2 Echocardiographic characteristics of the study population, stratified by
standard echo criteria for HCM
1,3

Normal screening echo (n = 64) Borderline HCM (n = 24) Definite HCM (n = 19) Test statistic* P-value
2D-TM Data: mean [SD]
IVSd (mm) 10.30 (2.17) 12.38 (2.36) 15.53 (4.50) F= 27.33 <0.0001
LVPWd (mm) 9.22 (1.67) 11.00 (2.57) 11.32 (2.31) F=11.79 <0.0001
IVS/LVPW ratio 1.13 (0.20) 1.17 (0.33) 1.38 (0.33) F=6.77 0.0017
LVIDd (mm) 48.86 (5.76) 50.42 (6.00) 47.16 (7.92) F= 1.45 0.239
LA diameter (mm) 34.75 (5.62) 38.98 (4.02) 36.72 (4.96) F= 5.73 0.0044
LVEF M Mode (%) 61.81 (7.08) 66.17 (7.46) 68.33 (11.82) F=5.67 0.0046
LVOT gradient (mmHg) 5.32 (1.87) 5.91 (2.39) 7.00 (3.27) F=3.35 0.0399
RWT (mm) 0.38 (0.06) 0.44 (0.07) 0.50 (0.08) F=26.78 <0.0001
MWT (mm) 10.62 (1.13) 13.42 (0.50) 17.63 (3.65) F= 118.46 <0.0001
Maximal LV wall dimensions in diastole:
Antero- septal wall (mm) 10.12 (1.37) 12.58 (1.10) 16.63 (3.39) F=93.87 <0.0001
Postero- septal wall (mm) 9.88 (1.32) 12.67 (1.27) 15.84 (4.57) F=55.64 <0.0001
Antero-lateral wall (mm) 9.22 (1.13) 10.83 (1.61) 11.53 (2.09) F=23.74 <0.0001
Posterior wall (mm) 9.25 (1.09) 10.96 (1.08) 11.68 (2.03) F=32.74 <0.0001
LV Mass (g) 172.55 (48.34) 230.29 (60.66) 268.53 (133.37) F=14.96 <0.0001
Pulsed Doppler
Peak E velocity (cm/s) 0.80 (0.17) 0.73 (0.22) 0.79 (0.14) F=1.60 0.206
Peak A velocity (cm/s) 0.58 (0.17) 0.58 (0.13) 0.60 (0.18) F=0.16 0.854
E/A ratio 1.49 (0.49) 1.31 (0.51) 1.45 (0.61) F=0.98 0.379
E deceleration time (ms) 187.87 (60.29) 203.50 (33.91) 220.11 (61.30) F=2.60 0.079
Tissue Doppler
Septal Sa (cm/s) 8.25 (2.35) 7.68 (2.48) 7.10 (1.99) F=1.54 0.220
Septal Ea (cm/s) 10.22 (3.33) 7.01 (3.29) 7.90 (3.90) F=8.02 0.0006
Septal Aa (cm/s) 8.89 (2.11) 8.96 (3.58) 8.09 (2.64) F=0.60 0.550
Lateral Sa (cm/s) 10.13 (3.38) 8.41 (3.14) 8.29 (2.44) F=3.18 0.047
Lateral Ea (cm/s) 12.87 (5.99) 9.95 (4.03) 11.19 (4.27) F=2.52 0.087
Lateral Aa (cm/s) 8.85 (2.99) 7.87 (3.39) 7.78 (3.50) F=1.06 0.350
Echocardiograph composite scores
Adjusted 2D-LVH score 36.28 (2.69) 39.71 (2.69) 39.03 (2.80) F=12.33 <0.0001
Spirito index (mm) 38.47 (3.71) 47.04 (3.03) 55.68 (9.53) F=90.81 <0.0001
Gandjbakhch risk score 2.78 (1.59) 0.95(3.77) 0.57 (2.59) F=11.91 <0.0001
* Comparisons across the strata of echo findings were made using ANOVA.
IVSd Interventricular septum diameter in diastole.
LVPWd Left ventricular posterior wall diameter in diastole.
LVIDd Left ventricular internal diameter in diastole.
LA Left atrium.
LVEF Left ventricular ejection fraction LVOT Left ventricular outflow tract.
RWT Relative wall thickness MWT Maximal wall thickness.
The results of the cardiac troponin assays are shown in Table 3, by screening outcome. In
total, 104 patients had valid results for the hsTnI assay, and 93 for the cTnI assay. Significant
increases in TnI both by the contemporary and highly-sensitive assay were seen across the
HCM strata. This graded association was also seen when 99th percentile cut points were
applied. A box plot displaying this significant increase in ln(hsTnI) is shown in Figure 1. This
relationship between both cTnI and hsTnI and echo-based measures of LV hypertrophy and
diastolic function was examined further using Pearsons correlation coefficient, and strong,
positive relationship were again noted between the measures of LV hypertrophy and TnI
(Additional file 1: Table S1).
Table 3 Description of the cardiac troponin and highly sensitive troponin findings in the
screening population
Normal screening echo Borderline HCM Definite HCM Test statistic; P-value
Sample size: 56 20 17
Cardiac Troponin I Log cTnI: mean(SD) 4.71 (0.01) 4.60 (0.34) 4.31 (0.94) F= 5.63; p= 0.005
Abnormal cTnI: n(%) 0 (0%) 1 (5%) 3 (18.8%) Fishers exact p= 0.006
Sample size: 63 22 19
High-sensitivity cardiac troponin I Log hsTnI: mean (SD) 0.62 (1.08) 1.34 (1.00) 1.94 (1.45) F=11.06; p<0.0001
Abnormal hsTnI: n(%) 1 (1.6%) 1 (4.6%) 4 (22.2%) Fishers exact p=0.008
HCM Hypertrophic cardiomyopathy.
Figure 1 Box plot of the natural log of highly-sensitive cardiac troponin I by HCM
groups as stratified by standard echo criteria. Footnote for Figure 1: p values shown are
from the Wilcoxon rank sum test. For the the difference in ln(hsTnI) between the no HCM
and Borderline change groups: z=2.47, p=0.013. For the the difference in ln(hsTnI) between
the Definite HCM and Borderline change groups: z=1.59, p=0.112. For the the difference in
ln(hsTnI) between the Definite HCM and no HCM groups: z=3.468, p=0.0005.
Figure 2 shows the association between the natural log of hsTnI and key measures of LV
mass (MWT, IVS:LVPWd ratio, LV mass and the Spirito score). Ordinary least-squares
regression lines were fitted, with adjusted R
2
values of up to 0.29 for the model with the
Spirito score as the dependent variable. Simple and multiple-adjusted logistic models for
possible or definite HCM by echo criteria [1,3] are shown in Table 4. For both models, the
odds ratio associated with hsTnI, but not cTnI, was statistically significant. Furthermore, the
models which included hsTnI had non-significant increases in AUROC when compared with
equivalent models with the cTnI assay as a covariable.
Figure 2 Scatterplot with fitted linear regression line, showing the association between
the natural log of highly sensitive cardiac troonin I with a. the IVS:LVPW ratio, b. the
MWT, c. the LV mass estimate and d.the Spirito index. Footnote for Figure 2: Regression
coefficient for the IVSd: LVPWd ratio was 0.008, 95% CI [0.52, 2.19], p=0.002, adjusted R
2

0.08. Regression coefficient for the LV maximal wall thickness was 0.20, 95% CI [0.13,
0.26], p<0.0005, adjusted R
2
0.25. Regression coefficient for the LV mass was 0.088, 95% CI
[0.005, 0.010], p<0.0005, adjusted R
2
0.26. Regression coefficient for the Spirito score was
0.08, 95% CI [0.06, 0.10], p<0.0005, adjusted R
2
0.29.
Table 4 Association of both standard and highly sensitive cardiac troponin I assays with
an echo diagnosis of definite HCM, using logistic regression analysis
Odds ratio (95% CI) P value Pseudo R2 AUROC (95% CI)
cTnI Models
Model 1* Natural log of cTnI 4.20 (0.94, 18.80) 0.060 0.102 0.66 (0.51, 0.82)
Model 2 ** 2.56 (0.54, 12.14) 0.236 0.197 0.76 (0.62, 0.91)
hsTnI Models
Model 1* Natural log of hsTnI 2.35 (1.39, 3.96) 0.001 0.173 0.78 (0.65, 0.90)
Model 2 ** 1.82 (1.02, 3.24) 0.042 0.231 0.81 (0.70, 0.93)
* Model 1 adjusted for age and sex.
** Model 2 adjusted for age, sex, presence of group 2 ECG abnormalities, and symptoms of
dyspnoea, chest pain, syncope or palpitations.
Footnote: For the ln(cTnI): comparison between AUROC in Model 1 vs Model 2: 2=1.90,
p=0.168. For the ln(hsTnI): comparison between AUROC in Model 1 vs Model 2: 2=1.03,
p=0.310. For the comparison between the AUROCs in Model 2 for the models with ln(cTnI)
and ln(hsTnI): 2= 0.87, p=0.351.
We examined the potential screening utility of the hsTnI assay in a screening setting for
HCM. Table 5 shows incremental though statistically non-significant gains in model R
2
and
AUROC when the hsTnI assay was added to the screening model, and there was a trend
towards an improvement in IDI with the enhanced screening model when compared to the
model without ln(hsTnI) . The sensitivity of the ln(hsTnI) enhanced screening model was
53.7% and specificity was 88.9%, with a positive predictive value of 75.9% and a negative
predictive value of 74.7%.
Table 5 HCM screening and the effect of the addition of the troponin measures
screening models, using logistic regression with boderline or definite HCM findings at
echo as the dependent variable
Model Covariables n Pseudo R2 AUROC (95% CI)
Simple model Age, sex and symptoms 104 0.177 0.75 (0.65, 0.86)
Screening model Age, sex, symptoms and Group 2 ECG changes 104 0.189 0.77 (0.67, 0.87)
Enhanced screening model with cTnI Age, sex, symptoms, Group 2 ECG changes and ln(cTnI) 104 0.201 0.75 (0.63, 0.86)
Enhanced screening model with hsTnI Age, sex, symptoms, Group 2 ECG changes and ln(hsTnI) 104 0.225 0.78 (0.69, 0.88)
Footnote: Integrated discrimination index (IDI) for the addition of the ln(cTnI) to the
Screening model is 0.025 (standard error 0.024), p=0.299. Integrated discrimination index
(IDI) for the addition of the ln(hsTnI) to the Screening model is 0.036 (standard error
0.019), p=0.056.
Discussion
Description of key findings
This study aimed to examine the association between cardiac troponin I and the clinical
diagnosis of hypertrophic cardiomyopathy in a high-risk screening population, with a focus
on the new highly-sensitive cTnI assay method. There was a clear and consistent graded
association between cTnI (measured both by the contemporary and highly-sensitive assays)
and measures of LV hypertrophy, whereas the association of the troponin measurements with
functional measures such as diastolic function were less clear. While improvements in IDI
and AUROC were noted when the hsTnI assay measure was added to a clinic-based
regression model to predict the finding of an echo finding consistent with a clinical diagnosis
of borderline or definite HCM, these improvements were not statistically significant.
Where this fits in the literature
There is emerging interest in the possibility of using highly-sensitive troponin measures in
risk stratification in cardiovascular diseases. Highly-sensitive troponin I has been shown to
contribute to athersclerotic CVD and heart failure risk in primary prevention populations,
even after adjustment for multiple traditional risk factors [20,21]. However, it is not clear
why troponins I and T may be elevated in HCM. Current theories include the concept that the
elevation may be due to myocyte necrosis from a mismatch between the hypertrophied
myocardium and a compromised coronary blood supply, or that the elevation is caused by the
underlying genetic abnormality [22].
Cardiac troponin assays have been previously established to be associated with degree of
hypertrophy in patients with known HCM [23]. CTnI is correlated with maximal LV wall
thickness in patients with hypertrophic cardiomyopathy [8]. Moreno et al. described an
outpatient population with HCM, in who 42% had an elevated hsTnT level, and patients with
higher hsTnT levels were more likely to have symptoms of dyspnoea and/or fibrosis on
cardiac MRI evaluation [9]. It has also been reported to be elevated in HCM caused by
Fabrys disease [24]. Cardiac troponin I has also been linked to outcome status in HCM, with
a combination of cTnI and BNP predicting adverse cardiovascular outcomes [25]. However,
the utility of cTnI and hsTnI in a HCM screening population has not previously been
evaluated. Furthermore, we are not aware of any previous study which has compared the
relative utility of the two assay types in such a population.
Strengths and limitations
This study reports the first examination of a new highly sensitive TnI assay in patients both
with, and at risk of, HCM. Furthermore, our analysis presents a novel potential use for cTnI
and hsTnI, using a high-risk screening population for HCM. The population was well
phenotyped, with echos read independently and in a blinded manner. Our study has some
limitations. The data described are cross-sectional data, and clinical outcome data are not yet
available. A cohort study on this population is ongoing. Other authors have used an analysis
endpoint of HCM genotype status. This was not consistently available for our patients, and
we note that HCM genotype may not be available in many clinical situations where a rapid
decision on risk status is required. An echocardiographic end-point has good face validity and
a well-established clinical application. Tissue and pulsed Doppler measures of diastolic
dysfunction were used in this study, and were seen not to have a consistent relationship with
cTnI or hsTnI. Use of a further robust measure such as speckle-tracking echocardiography
should however be considered for future studies. The sample size was small, and therefore
this study aimed to establish proof of concept only [17]. Whilst small improvements in
clinic stratification were seen using hsTnI, these were not statistically significant. Further
study recruitment is underway. The study sample are from a high-risk screening population,
and it is not known how hsTnI may add to HCM diagnosis in population-screening samples.
Implications for practice
This study shows a potential role for cardiac troponin assays, in particular assays of hsTnI, in
HCM screening. This finding needs to be replicated in other studies and also ideally
examined in a prospective cohort setting. We examined a high-risk screening population
for HCM. Population screening for inherited cardiac diseases is a topic of much debate, and
there is particular focus on screening young athletes, in whom both a questionnaire and ECG
are recommended [26]. However, identification of HCM and risk stratification can be
clinically challenging. Furthermore, in young patients and sportspersons in particular, the
ramifications of a HCM diagnosis can be substantial [27]. Highly-sensitive troponin assays
are relatively inexpensive, and will be widely available in the future. This study provides a
rationale for further investigation of the utility of this measure in the identification and
management of patients with HCM.
Conclusions
This is the first study to examine a new hsTnI assay in persons at risk of HCM. Both cTnI
and hsTnI are shown to have a graded, positive association with measures of muscle mass in
persons with and at risk of HCM. There was a non-significant increase in AUROC with the
addition of hsTnI to the clinic screening model. The cTnI and new hsTnI assay may add to
ECG- and symptom-based identification of HCM in at-risk families, although further larger
scale studies will be required to evaluate this.
Competing interests
The authors declare that they have no competing interests.
Authors contributions
CMcG, AR, MC, PD, MF, JG and NM designed the study. CMcG, AR and SL collected the
data. CMcG, SL, HT and MF performed the TnI analyses. CMcG and SL performed the data
analysis and wrote the manuscript. All co authors provided comments on the manuscript. All
authors read and approved the final manuscript.
Acknowledgements
CMcG is in receipt of a UCD Edwards Lifesciences Newman Fellowship. We would like to
acknowledge the assistance of colleagues in the Departments of Cardiology and of Clinical
Biochemistry (Dr Orla Constant, Dr James ONeill, Dr Ted Keelan, Ms Catherine ODonnell,
Ms Brenda Fleming, Ms Berna Guest and Mr Des McGoldrick), as well as the contribution of
the patients who generously agreed to participate in the study.
Funding
This work was supported through the Mater Foundation (which supports the clinics
provision of cardiac screening to at-risk families), and the Irish Heart Foundations Noel
Hickey Bursary. CMcG was in receipt of an Edwards Lifesciences Newman Scholarship
through University College Dublin. Cardiac troponin assay kits were provided by Abbott
Diagnostics, however the company had no role in the study protocol and design, data
collection, sample analysis, data analysis or manuscript writing; and the decision to submit
for publication was made by the research team alone.
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Additional file
Additional_file_1 as DOC
Additional file 1: Table S1 Pair-wise correlation between the cardiac troponin I
measurements and selected key echocardiographic features and scores.
Figure 1
Figure 2
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