Troponin as ischemic biomarker is related with all three echocardiographic risk factors for sudden death in hypertrophic cardiomyopathy (ESC Guidelines 2014)
Hładij et al. Cardiovascular Ultrasound
Troponin as ischemic biomarker is related with all three echocardiographic risk factors for sudden death in hypertrophic cardiomyopathy (ESC Guidelines 2014)
Rafał Hładij 0 2
Renata Rajtar-Salwa 0 2
Paweł Petkow Dimitrow 1 2
0 Equal contributors
1 II Klinika Kardiologii CMUJ , ul. Kopernika 17, 31-501 Kraków , Poland
2 2nd Department of Cardiology, Jagiellonian University Medical College , Kraków , Poland
Background: Sudden cardiac death (SCD) risk stratification is the most important preventive action in patients with hypertrophic cardiomyopathy (HCM). The identification of the ischemia biomarker high sensitive troponin I (hs-TnI) role for this arrhythmic disease may provide additional information for SCD risk stratification. The aim of the study was to compare echocardiographic parameters (prognostic for risk stratification of SCD in HCM) among two subgroups of HCM patients: with elevated hs-TnI versus non-elevated hs-TnI level. Methods: In 51 HCM patients (mean age 39 ± 8 years, 31 males and 20 females) an echocardiographic examination, including the stimulating maneuvers to provoke maximized LVOT gradient, was performed. The hs-TnI was measured 24 h later. Results: By comparing two subgroups of patients, 26 members with hs-TnI positive versus 25 with hs-TnI negative, the study showed that the values of all three parameters were greater: provocable left ventricular outflow tract gradient (LVOTG) - 49.1 ± 45.9 vs 25.5 ± 24.8 mmHg, p = 0.019; left atrial diameter - 50.1 ± 9.6 vs 43.9 ± 9.8 mmHg, p = 0.041; maximal LV thickness - 22.1 ± 5.3 vs 19.9 ± 34 mm, p = 0.029. Conclusion: The increased value of all three echocardiographic parameters used as risk factors for SCD (ESC Guidelines) is related to the elevated level of hs-TnI in HCM. Due to the high LVOTG - great hs-TnI relationship, exercise stress, both diagnostic and even rehabilitation/training, should be monitored by biomarker control.
Hypertrophic cardiomyopathy; Troponin; Echocardiography
Among risk factors of SCD in HCM in current ESC
Guidelines (1), three echocardiographic parameters are
included. These echocardiographic parameters are
precise due to unequivocal, accurate measurable, in current
moment of risk stratification using risk calculator [
This calculator for sudden cardiac death risk does not
include any biomarker. Calculator also did not include
either the ischemic biomarker or signs and symptoms
for myocardial ischemia. However, ischemic response to
stress revealed by echocardiographic methods becomes
more and more important [
Very recently, a relationship between nonsustained
ventricular tachycardia (ECG-Holter risk factor) and
elevated troponin level has been reported [
High-sensitive troponin I (hs-TnI) is aprecise
biomarker for the detection of myocardial ischemia. In
previous HCM studies, the measurements of hs-Tn were
performed only at a resting (without stress)
echocardiography and not timely synchronized with maneuvers to
provoke LVOTG by natural stimuli reflecting daily
common physical activities for patients [
The aim of this study was compare to three
echocardiographic parameters (risk factors for SCD: provocable
LVOTG, left atrial diameter, maximal LV thickness at
end diastole) between subgroups divided by the border
value of h-s TnI concentrations in HCM patients. The
cut-off value 19,5 ng/l was used according to producer
instruction (bioMerieux VIDAS® High sensitive Troponin I). The
99th percentile of a presumably healthy population, the
recommended cut-off has been defined at 19,5 ng/L [
We have compared echocardiographic parameters
between subgroup patients with elevated hs-TnI level
versus subgroup patients with non-elevated hs-TnI level.
Consecutive patients with HCM were recruited to the
study. All patients fulfilled conventional diagnostic
criteria for HCM. The exclusion criteria were as follows:
ST-segment or non-ST-segment elevation myocardial
infarction (recent or previous), significant coronary
stenosis on coronary angiography, or renal failure.
The final sample included 51 patients with HCM
(mean ± SD age, 39 ± 8 years; 30 men and 21 women).
Coronary angiography was performed (due to
indications) in 11 patients (result was normal or insignificant
coronary artery stenosis <50%).
The patients on current pharmacotherapy were
examined in the following 24-h cycle as follows: 8 a.m.
echocardiography with LVOTG provocation by natural
stimuli (orthostatic test and Valsalva test [
]provocable LVOTG is more preference than resting in
SCD calculator ) day phase physical activity with
probably episodes of provocable LVOTG
(unmeasurable), night phase period as a potential time for the rise
of troponin, which level has been measured after night
at 8 a.m. So far, no studies have used the following
protocol. The patients has been asked to performed your
common day physical activity and nocturnal resting.
This protocol seems to be reasonable because hs-TnI
levels may be related to the dynamic and labile nature of
LVOTG with fluctuating peaks during the day time
(provoked LVOTG as a potential cause for myocardial
ischemia). During the first stage of our study we did not
use upright exercise stress test to provoke LVOTG [
because previous study had reported exercise-related Tn
Methodology of measurement of echocardiographic
parameters has been based on ESC Guidelines [
increased ventricular wall thickness can be found at any
location, the presence, distribution and severity of
hypertrophy should be documented using a standardized
protocol for cross-sectional imaging from several
projections. Correct orientation and beam alignment along
orthogonal planes are essential to avoid oblique sections
and over-estimation of wall thickness. Measurements of
LV wall thickness should be performed at end-diastole,
preferably in short-axis views. The most relevant
parameter is the maximum LV wall thickness at any level [
Accordingly to ESC Guidelines [
] and previous Italian
] we use anteroposterior LA diameter.
The workflow of echocardiographic examination has
been as follows:
a) standard echo examination in resting condition in
supine position (the last stage of examination was
LVOTG measurement using 5-chamber apical
b) immediately, Valsalva maneuver was perform in
supine position with LVOTG measurement
c) patients were asked to stand up with their left hand
on their head
d) LVOTG was measured in 5-chamber apical when
patient was in standing position
The study protocol was approved by the local institutional
review board (Komisja Bioetyki Jagiellonian University
KBET/119/B/2017). Informed consent was obtained from
Normally distributed continuous variables were
presented as mean ± SD. Differences between two groups
were assessed using independent t test. Correlations
between hs-TnI levels and echocardiographic parameters
were assessed using the Pearson correlation coefficient.
A P value of less than 0.05 was considered significant.
The characteristics of patients are displayed in Table 1.
Hs-TnI was detected in all HCM patients and patients
with an abnormal level > 19,5 ng/l were defined as
positive troponin subgroup.
By comparing the hs-TnI positive versus negative
subgroups, the values of all three parameters were
greater: left atrial diameter; maximal LV thickness,
provocable LVOTG. Also, resting LVOTG was greater in
hs-TnI positive subgroup (Table 2).
The Pearson correlations were statistically significant
between provocable LVOTG and hs-TnI (r = 0.39,
p < 0.05) as well as between resting LVOTG and hs-TnI
(r = 0.37 p < 0.05).
Best to our knowledge, current study is the first ever
report about relationship between elevated hs-TnI and all
three echocardiographic risk factors (measurements was
timely synchronized) for sudden death in hypertrophic
cardiomyopathy (ESC Guidelines 2014).
The impact of stress echocardiography in HCM is
limited by the lack of standardization and outcome
data. ECS guidelines recommend stress
echocardiography solely for the evaluation of LVOT [
large-scale registry data show that SE positivity for
ischemic criteria (such as new wall motion
abnormalities and coronary flow velocity reserve), rather than
inducible gradients predict adverse outcome in HCM
]. In a large study [
], mortality was predicted using
criteria for detecting ischemia on stress
echocardiography. The authors concluded that stress
echocardiography has an important prognostic role in patients
with HCM, with ischemic endpoints showing a
greater predictive accuracy than hemodynamic
There is no unequivocal data regarding the
hemodynamic mechanism for myocardial ischemia
diagnosed with hs-TnI release in HCM. We suspect that
elevated hs-TnI levels (related to episodes of provocable
LVOT) are quite common during the daily activities of
patients with HCM (even in pharmacotherapy).
Therefore, we investigate the presence of and potential
hemodynamic mechanism underlying the increased
hs-TnI levels in relation to the findings on resting and
Previously, in experimental studies (resting supine
position) ischemia was induced by rapid atrial pacing
and beta-receptor stimulation [
invasive measured marker of myocardial ischemia was
lactate metabolism (myocardial lactate extraction
indicated the difference between arterial and great cardiac
vein lactate contents) [
]. Negative difference was
defined as lactate production and preciously indicate
In HCM patients with LVOTG [
coronary flow reserve was exhausted at a heart rate of 130
beats/min; higher heart rates resulted in more severe
metabolic evidence of ischemia (lactate production
instead consumption) with all patients experiencing
chest pain. At a heart rate of 150, most patients with
basal LVOTG demonstrated an actual decline in
coronary flow, which correlated with more severe metabolic
evidence of ischemia [
]. In a study by Cannon et al.
], majority patients with HCM with reversible
thallium-201 abnormalities during exercise showed
metabolic evidence of myocardial ischemia during rapid
pacing (myocardial lactate production) associated with
increase of LV end diastolic pressure. Beta-receptor
stimulation increased LVOTG parallel with lactate
] and oppositely surgical reduction of
LVOTG was associated with a beneficial shift from
lactate production to consumption [
In previous study [
] ischemic injury assessed by
CKMB (long-term follow-up was started in 1987/88 years)
was related with increasing left atrial diameter. In our
study without follow-up, we use more sensitive
biomarker and increased TnI level is related with greater
left atrial diameter.
Currently, we can use an almost a perfect marker of
ischemia, sampled from a peripheral vein i.e. troponin
measured by the high-sensitive method.
In a recent review by McCarthy et al. [
], the utility of
hs-Tn assessment in arrhythmic disease is only at the
initial stage, but it has been proposed as a valuable screening
marker for patients with HCM at a high risk of SCD.
Regular training exercise has recently been
recommended for selected patients with HCM [
]. In our
opinion, based on the association between provocable
LVOTG and elevated troponin level in patients with
HCM, we suggest that any exercise stress test in HCM
patients (performed either for training or diagnostic
purposes) should be controlled by troponin level
measurements 6 and 12 h after the exercise).
Our study has several limitations. First, the current
pharmacological treatment was maintained, and
particularly β-blockers were not withdrawn. In our pilot study,
we aimed to make the first-ever observation on the
correlation between hs-TnI release and timely
synchronized findings on echocardiography. Our preliminary
study showed that β-blocker withdrawal or specially
performed exercise test might not be safe among this
group of patients. In future studies, we will attempt to
increase the dose and use only one type of a β-blocker
to decrease ischemia burden and the risk of troponin
release in exercise test. We are going to perform upright
exercise with LVOTG measurement at peak and
postexercise in upright position [
We decided to measure hs-TnI levels only once
because our pilot study was conducted in an outpatient
setting. The optimal protocol, that is, 48-h profile of
troponin measurement with the assessment of troponin
with echocardiographic examination every 8 h, would
require the in-hospital setting for the study and would be
more costly. Moreover, only an outpatient-based study
provides an opportunity to assess patients during their
common daily physical activities of patients, however
daily activities between the patients were not well
standardized by for example by questionnaire. The
patients were asked to perform their common daily
physical activities and nocturnal resting.
The increased value of all three echocardiographic
parameters using as risk factors for sudden death are
related to the elevated level of h-s troponin-I in HCM.
These findings suggest that hs-Tn may be useful as an
additional biomarker for better risk stratification in HCM.
Additionally, we have postulated that every exercise test in
HCM should be controlled by the measurement of the
troponin level after 8–12 h from the stress test.
ESC: European Society of Cardiology; HCM: Hypertrophic cardiomyopathy;
Hs-TnI: High sensitivity troponin I; LVOTG: Left ventricular outflow tract
gradient; SCD: Sudden cardiac death
RH contributed to conception, contributed to acquisition and analysis, gave
final approval. RSR contributed to conception and design, contributed to
acquisition, analysis, and interpretation, critically revised manuscript gave
final approval. PPD contributed to conception and design, contributed to
acquisition, analysis, and interpretation, drafted manuscript, critically revised
manuscript, gave final approval.
Consent for publication
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
1. Authors/Task Force members, Elliott PM , Anastasakis A , Borger M , Borggrefe M , Cecchi F , Charron P , et al. 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC) . Eur Heart J . 2014 ; 35 : 2733 - 79 .
2. Ciampi Q , Olivotto I , Gardini C , D'Andrea A , Scali MC , Cortigiani L , et al. Prognostic role of stress echocardiography in hypertrophic cardiomyopathy: The International Stress Echo Registry . Int J Cardiol . 2016 ; 219 : 331 - 8 .
3. Picano E , Ciampi Q , Citro R , D'Andrea A , Scali MC , Cortigiani L , et al. Stress echo 2020 : the international stress echo study in ischemic and non-ischemic heart disease . Cardiovasc Ultrasound . 2017 ; 15 : 3 .
4. Hładij R , Rajtar-Salwa R , Dimitrow PP. Associaton of elevated troponin levels with increased heart rate and higher frequency of nonsustained ventricular tachycardia in hypertrophic cardiomyopathy . Pol Arch Intern Med . 2017 ; 126 : 445 - 7 .
5. Kubo T , Kitaoka H , Yamanaka S , Hirota T , Baba Y , Hayashi K , et al. Significance of high-sensitivity cardiac troponin T in hypertrophic cardiomyopathy . J Am Coll Cardiol . 2013 ; 62 : 1252 - 9 .
6. Hasler S , Manka R , Greutmann M , Gämperli O , Schmied C , Tanner F , et al. Elevated high-sensitivity troponin T levels are associated with adverse cardiac remodelling and myocardial fibrosis in hypertrophic cardiomyopathy . Swiss Med Wkly . 2016 ; 146 : w14285 .
7. Kawasaki T , Sakai C , Harimoto K , Yamano M , Miki S , Kamitani T. Usefulness of high-sensitivity cardiac troponin and brain natriuretic peptide as biomarkers of myocardial fibrosis in patients with hypertrophic cardiomyopathy . Am J Cardiol . 2013 ; 112 : 867 - 72 .
8. Moreno V , Hernández-Romero D , Vilchez J , García-Honrubia A , Cambronero F , Casas T , et al. Serum levels of high-sensitivity troponin T: a novel marker for cardiac remodeling in hypertrophic cardiomyopathy . J Card Fail . 2010 ; 16 : 950 - 6 .
9. Chenevier-Gobeaux C , Bonnefoy-Cudraz É , Charpentier S , Dehoux M , Lefevre G , Meune C , Ray P , SFBC, SFC, SFMU ' Troponins' workgroup. High-sensitivity cardiac troponin assays: answers to frequently asked questions . Arch Cardiovasc Dis . 2015 ; 108 : 132 - 49 .
10. Dimitrow PP , Bober M , Michałowska J , Sorysz D. Left ventricular outflow tract gradient provoked by upright position or exercise in treated patients with hypertrophic cardiomyopathy without obstruction at rest . Echocardiography . 2009 ; 26 : 513 - 20 .
11. Dimitrow PP , TO C. Standing position alone or in combination with exercise as a stress test to provoke left ventricular outflow tract gradient in hypertrophic cardiomyopathy and other conditions . Int J Cardiol . 2010 ; 143 : 219 - 22 .
12. Dimitrow PP , Cotrim C , TO C. Need for a standardized protocol for stress echocardiography in provoking subaortic and valvular gradient in various cardiac conditions . Cardiovasc Ultrasound . 2014 ; 12 : 26 .
13. Pop GA , Cramer E , Timmermans J , Bos H , Verheugt FW . Troponin I release at rest and after exercise in patients with hypertrophic cardiomyopathy and the effect of betablockade . Arch Cardiol Mex . 2006 ; 76 : 415 - 8 .
14. Nistri S , Olivotto I , Betocchi S , Losi MA , Valsecchi G , Pinamonti B , et al. Prognostic significance of left atrial size in patients with hypertrophic cardiomyopathy (from the Italian Registry for Hypertrophic Cardiomyopathy) . Am J Cardiol . 2006 ; 98 : 960 - 5 .
15. Cannon RO 3rd, Schenke WH , Maron BJ , Tracy CM , Leon MB , Brush JE Jr, et al. Differences in coronary flow and myocardial metabolism at rest and during pacing between patients with obstructive and patients with nonobstructive hypertrophic cardiomyopathy . J Am Coll Cardiol . 1987 ; 10 : 53 - 62 .
16. Udelson JE , Cannon RO 3rd, Bacharach SL , Rumble TF , Bonow RO . Betaadrenergic stimulation with isoproterenol enhances left ventricular diastolic performance in hypertrophic cardiomyopathy despite potentiation of myocardial ischemia. Comparison to rapid atrial pacing . Circulation . 1989 ; 79 : 371 - 82 .
17. Cannon RO 3rd, Dilsizian V , O'Gara PT , et al. Myocardial metabolic, hemodynamic, and electrocardiographic significance of reversible thallium-201 abnormalities in hypertrophic cardiomyopathy . Circulation . 1991 ; 83 : 1660 - 7 .
18. Cannon RO 3rd, McIntosh CL , Schenke WH , Maron BJ , Bonow RO , Epstein SE , et al. Effect of surgical reduction of left ventricular outflow obstruction on hemodynamics, coronary flow, and myocardial metabolism in hypertrophic cardiomyopathy . Circulation . 1989 ; 79 : 766 - 75 .
19. Hamada M , Shigematsu Y , Ohtani T , Ikeda S. Elevated cardiac enzymes in hypertrophic cardiomyopathy patients with heart failure - a 20-year prospective follow-up study . Circ J . 2016 ; 80 : 218 - 26 .
20. McCarthy CP , Yousuf O , Alonso A . High-sensitivity troponin as a biomarker in heart rhythm disease . Am J Cardiol . 2017 ; 119 : 1407 - 13 .
21. Saberi S , Wheeler M , Bragg-Gresham J , Hornsby W , Agarwal PP , Attili A , et al. Effect of moderate-intensity exercise training on peak oxygen consumption in patients with hypertrophic cardiomyopathy: a randomized clinical trial . JAMA . 2017 ; 317 : 1349 - 57 .
22. Reant P , Dufour M , Peyrou J , Reynaud A , Rooryck C , Dijos M , et al. Upright treadmill vs. semi-supine bicycle exercise echocardiography to provoke obstruction in symptomatic hypertrophic cardiomyopathy: a pilot study . Eur Heart J Cardiovasc Imaging . 2017 . doi: 10 .1093/ehjci/jew313. [Epub ahead of print].
23. Reant P , Lafitte S , Reynaud A . How to perform stress/exercise echocardiography in -hypertrophic cardiomyopathy? Acta Cardiol . 2017 ; 72 : 265 - 6 .
24. Dimitrow PP , Rajtar-Salwa R . Obstructive form of hypertrophic cardiomyopathy-left ventricular outflow tract gradient: novel methods of provocation, monitoring of biomarkers, and recent advances in the treatment . Biomed Res Int . 2016 ; 2016 : 1575130 .