Effects of hyperaemia on left ventricular longitudinal strain in patients with suspected coronary artery disease
Effects of hyperaemia on left ventricular longitudinal strain in patients with suspected coronary artery disease
P. Garg 0
R. Aziz 0
T. Al Musa 0
D. P. Ripley 0
P. Haaf 0
J. R. J. Foley 0
P. P. Swoboda 0
G. J. Fent 0
L. E. Dobson 0
J. P. Greenwood 0
S. Plein 0
0 Multidisciplinary Cardiovascular Research Centre & Division of Biomedical Imaging, Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds , Leeds , UK
Aims Myocardial perfusion imaging during hyperaemic stress is commonly used to detect coronary artery disease. The aim of this study was to investigate the relationship between left ventricular global longitudinal strain (GLS), strain rate (GLSR), myocardial early (E') and late diastolic velocities (A') with adenosine stress first-pass perfusion cardiovascular magnetic resonance (CMR) imaging. Methods and results 44 patients met the inclusion criteria and underwent CMR imaging. The CMR imaging protocol included: rest/stress horizontal long-axis (HLA) cine, rest/stress first-pass adenosine perfusion and late gadolinium enhancement imaging. Rest and stress HLA cine CMR images were analysed using feature-tracking software for the assessment of myocardial deformation. The presence of perfusion defects was scored on a binomial scale. In patients with hyperaemia-induced perfusion defects, rest global longitudinal strain GLS (-16.9 ± 3.7 vs. -19.6 ± 3.4; p-value = 0.02), E' (-86 ± 22 vs. -109 ± 38; p-value = 0.02), GLSR (69 ± 31 vs. 93 ± 38; p-value = 0.01) and stress GLS (-16.5 ± 4 vs. -21 ± 3.1; p < 0.001) were significantly reduced when compared with patients with no perfusion defects. Stress GLS was the strongest independent predictor of perfusion defects (odds ratio 1.43 95% confidence interval 1.14-1.78, p-value <0.001). A threshold of -19.8% for stress GLS demonstrated 78% sensitivity and 73% specificity for the presence of hyperaemia-induced perfusion defects. Conclusions At peak myocardial hyperaemic stress, GLS is reduced in the presence of a perfusion defect in patients with suspected coronary artery disease. This reduction is most likely caused by reduced endocardial blood flow at maximal hyperaemia because of transmural redistribution of blood flow in the presence of significant coronary stenosis.
Cardiovascular magnetic resonance; Coronary artery disease; Adenosine; Perfusion imaging; Left ventricular function
Cardiovascular magnetic resonance (CMR) imaging can
detect obstructive coronary artery disease (CAD) by imaging
the left ventricular (LV) passage of a contrast bolus
during pharmacologically induced myocardial hyperaemia [
Although hyperaemic stress does not usually induce
myocardial ischaemia per se, myocardium supplied by a
significantly stenosed coronary artery shows reduced
hyperaemic contrast uptake compared with normal myocardium.
Hyperaemia also leads to a redistribution of myocardial
blood flow (MBF) between the endocardial and epicardial
]. An endocardial to epicardial gradient of blood
Fig. 1 Illustration
demonstrating how fibre orientation of the
left ventricle corresponds to
perfusion defect gradient (high in
sub-endocardium and lower in
flow exists at rest, reflecting the higher metabolic
activity of the endocardial layer [
]. In health,
pharmacologically induced maximal hyperaemia increases MBF in all
myocardial layers although the endocardial to epicardial
gradient diminishes as MBF maximises in all myocardial
layers. In the context of functionally significant epicardial
CAD, hyperaemia leads to a redistribution of MBF from
the endocardium to the epicardium, leading to relative
endocardial ischaemia, or transmural myocardial steal ([
Fig. 1). Thanks to its high in-plane spatial resolution, this
transmural perfusion gradient can be demonstrated in vivo
with first-pass myocardial perfusion CMR and a transmural
perfusion gradient of 20% can accurately predict
haemodynamically significant CAD as defined by fractional flow
reserve (FFR) on invasive coronary angiography [
Myocardial strain imaging allows quantification of subtle
changes of LV function that typically precede a reduction in
LV ejection fraction (EF) [
]. Myocardial deformation can
be studied with CMR feature tracking (FT), in which strain
is derived from routine cine acquisitions without the need
for the previously used tagging methods [
]. FT allows
accurate and robust assessment of mainly LV global
longitudinal strain [
]. Because longitudinal myocardial fibres are
predominantly located in the sub-endocardium, they may
be preferentially affected in myocardial ischaemia and by
transmural steal during hyperaemia in the presence of
significant CAD. The association of differential abnormalities
in local left ventricular function assessed by myocardial
strain and peak myocardial hyperaemia in the presence or
absence of perfusion defects has not been established yet.
Therefore, the purpose of this study was to investigate
the relationship between left ventricular global longitudinal
strain (GLS), strain rate (GLSR), myocardial early (E’) and
late diastolic velocities (A’) with adenosine stress first-pass
perfusion CMR and determine which strain parameter is
most strongly associated with the presence of a perfusion
This was a prospective-cohort study of patients presenting
to the rapid access chest pain clinic in a single tertiary
cardiology centre, who were referred on clinical grounds for
a stress CMR study for the evaluation of suspected CAD.
Exclusion criteria were: estimated glomerular filtration rate
<30 ml/min/1.73 m2, non-ischaemic cardiomyopathy or any
contraindication to CMR imaging. All patients gave written
informed consent for their data to be used in this study.
The study protocol was approved by the local research
ethics committee. The present study complied with the
Declaration of Helsinki and all patients gave written informed
CMR protocol included: rest/stress horizontal long-axis
(HLA) cine, rest/stress first-pass adenosine perfusion and
late gadolinium enhancement imaging. CMR protocol is
detailed in the online Supplementary File 1.
CMR images were anonymised, which included the
removal of dates of acquisition and any identifiable data.
Cines, perfusion and LGE images were blindly evaluated
offline using commercially available software (cvi42 v5.1,
Circle Cardiovascular Imaging Inc., Calgary, Canada) by
one observer (RA). Left ventricular volumes and ejection
fraction (EF) were analysed from short-axis cine images
using standard methods [
]. Infarct location was determined
by LGE imaging, according to standard guidelines [
Feature tracking strain analysis (rest and stress)
Strain analysis was performed using a cvi42 (v5.1) feature
tracking (FT) module in a semi-automated manner (Fig. 2;
]). FT analysis was done by two observers (GF and PG).
For resting cines, left ventricular endocardial and
epicardial borders were manually contoured in end-diastole from
both long-axis cines (HLA and VLA). Stress global
longitudinal strain parameters were derived from HLA cines
only as no VLA images were acquired in order to minimise
the duration of adenosine infusion. Peak GLS, GLSR, E’
and A’ were recorded per case.
Perfusion images were independently analysed by two
experts in perfusion analysis with greater than 3-years’
experience each (TAM and DPR). Each expert reported on the
presence of inducible stress perfusion defects that were not
present on rest perfusion images and with no corresponding
scar on LGE images. In case of disagreement between the
two observers, a third independent expert analysed the
images, and a discussion of all observers took place to reach
a unanimous decision (PG). Studies in which a unanimous
decision could not be reached were excluded. On stress
perfusion imaging, an area of decreased signal intensity when
compared with remote myocardium and the presence of an
endocardial to epicardial perfusion gradient were classified
as a perfusion defect [
Statistical analysis and sample size estimates
Statistical analysis was performed using IBM SPSS
Statistics 21.0. Continuous variables were expressed, as mean ±
SD. Normality of quantitative data was established using
the Shapiro-Wilk test. Demographic comparisons between
two groups of patients (with and without perfusion defect)
were performed with an independent samples t-test. The
Data are presented as mean (standard deviation) or as numbers (%), unless otherwise indicated. P-value <0.05 was taken as significant
A’ myocardial late diastolic velocity, CABG coronary artery bypass grafting, CMR cardiovascular magnetic resonance, E’ myocardial early diastolic
velocity, ECG electrocardiogram, EDV end-diastolic volume, EF ejection fraction, ESV end-systolic volume, GLS global longitudinal strain,
GLSR global longitudinal strain rate, LV left ventricular, SV stroke volume
rest of the statistical methods are detailed in the online
Supplementary File 1.
characteristics, including myocardial infarction, were not
significantly different in both groups.
A total of 50 patients were recruited; 4 patients had
equivocal perfusion results, resulting in exclusion from the study
and 2 patients were claustrophobic. From the remaining
44 patients, 22 patients had an inducible perfusion
defect, and 22 patients had no inducible perfusion defect.
The two independent graders agreed on the categorisation
of all cases with no arbitration required. The
demographics, clinical data and baseline CMR results are shown in
Tab. 1. There were no differences based on gender, age or
characteristics present between the groups. Baseline CMR
Feature tracking analysis
All cine images were of adequate quality for FT analysis.
Fig. 2 demonstrates two cases from the study. Rest GLS,
GLSR, E’ and stress GLS were significantly lower in the
group with a perfusion defect compared with the no
perfusion defect group (Tab. 1). Notably, rest GLS was not
significantly different in patients without previous
myocardial infarction and with/without ischaemia (Tab. 2; Fig. 3).
The absolute change in rest versus stress GLS
demonstrated an increase in GLS in patients without perfusion
defects but a reduction in GLS at stress in patients with a
perfusion defect (–1.6 ± 3.1 versus 0.5 ± 3.8, p-value = 0.05).
Other strain parameters, GLSR (–2.8 ± 77 versus –12 ± 31,
p-value = 0.60), E’ (13 ± 45 versus 22 ± 40, p-value =
Data are presented as mean (standard deviation) or as numbers (%), unless otherwise indicated. P-value <0.05 was taken as significant
A’ myocardial late diastolic velocity, E’ myocardial early diastolic velocity, GLS global longitudinal strain, GLSR global longitudinal strain rate,
LGE+ late gadolinium enhancement present, LGE– late gadolinium enhancement absent, MI myocardial infarction
0.45), A (27 ± 65 versus 13 ± 29, p-value = 0.43) did not
show significant changes between rest and stress.
Influence of previous myocardial infarction
Patients with previous myocardial infarction on LGE
imaging had lower rest GLS (–16 ± 3% vs. –20 ± 4%, p-value =
0.007) and stress GLS (–17 ± 4% vs. –20 ± 4%, p-value =
0.02). However, patients with previous myocardial
infarction did not show more inducible perfusion defects than
those without previous myocardial infarction (odds ratio
(OR) 0.38, p-value = 0.13).
Receiver operating characteristic curves analysis
Tab. 3 details the diagnostic performance for each of the
parameters. Fig. 4 displays the receiver operating
characteristic (ROC) plots. Stress GLS displayed a slightly better,
though not statistically significant, diagnostic performance
compared with rest GLS (Tab. 3; Fig. 4). A strain model
comprising of rest GLS, GLSR, E’ and stress GLS
demonstrated significant superiority to rest GLS alone. The strain
model displayed a sensitivity of 95% and specificity of 68%
to detect perfusion defects.
Data as presented as mean (standard deviation) or as numbers (%), unless otherwise indicated. P-value <0.05 was taken as significant
A’ myocardial late diastolic velocity, AUC area under the curve, CI confidence interval, CMR cardiovascular magnetic resonance, E’ myocardial
early diastolic velocity, GLS global longitudinal strain, GLSR global longitudinal strain rate
aModel comprising of strain parameters associated to the presence of perfusion defect in univariate analysis: rest GLS, rest GLSR, rest E’ and
In the logistic regression analysis, stress GLS demonstrated
the best independent association with the presence of a
perfusion defect of the parameters tested (OR 1.43 95% CI
1.14–1.78, p-value <0.001) (Online Supplementary File 2).
The logistic regression strain model was independently
associated with presence of perfusion defect (p-value <0.001)
when compared with other individual myocardial strain
The main novel findings of this study are: 1) at peak
myocardial hyperaemia, GLS is reduced in patients with
inducible perfusion defects; 2) stress GLS is most strongly
associated with the presence of a perfusion defect; and
3) a cut-off value of –19.8% for stress GLS demonstrates
77% sensitivity and 73% specificity for the presence of
a perfusion defect.
Myocardial ischaemia initially affects the endocardium
and progresses to the sub-epicardial layers in a ‘wave front’
]. High resolution adenosine stress myocardial
perfusion CMR can demonstrate a transmural gradient of
myocardial perfusion in patients with flow limiting CAD,
representing the redistribution of myocardial blood flow
from the sub-endocardium to the sub-epicardium.
Sub-endocardial fibres are structurally longitudinal fibres [
therefore predominantly contribute to the longitudinal
function of the left ventricle [
]. The main findings of the
present study are consistent with these known concepts.
We found that global longitudinal function assessed by GLS
was adversely affected during adenosine stress in patients
with perfusion defects while GLS in patients with no
perfusion defects increased during hyperaemia. The most likely
mechanism underpinning this observation is that relative
ischaemia of the sub-endocardial myocardial layer
(‘transmural myocardial steal’) affects longitudinal fibre function
during hyperaemia and thus differentially reduces
longitudinal LV function.
In patients with evidence of myocardial infarction on
LGE imaging, rest GLS, GLSR and E’ were also
correlated with the presence of perfusion defects, however, these
resting strain parameters did not discriminate between
patients with and without perfusion defects in the absence of
previous myocardial infarction. Like ischaemia, myocardial
infarction predominantly affects the endocardial layer and
a longitudinal myocardial strain and a reduction in resting
myocardial deformation can therefore be expected. The
correlation with the presence of an inducible perfusion defect
is likely to be caused by co-existing CAD in other
territories or peri-infarct ischaemia, both of which were common
in the present population in patients with prior MI.
However, resting strain parameters are not reliable markers of
inducible ischaemia as shown by the lack of correlation with
perfusion defects in patients without myocardial infarction.
A strain model comprising of rest GLS, GLSR, E’ and
stress GLS performed slightly better in this study than stress
GLS alone in linear regression (Tab. 3), but was not
statistically superior to individual parameters in area under the
curve (AUC) analysis (p > 0.05). As the strain model
requires multiple strain analyses, the use of stress GLS alone
may be a more practical approach for clinical studies.
Previous echocardiographic studies have reported
findings that are consistent with our observations. Liang et al.
found that rest peak systolic strain rate (equivalent to GLSR
in our study) and peak early diastolic strain rate (E’ in
our study) were significantly lower in patients with
significant CAD (>70% stenosis) than controls [
]. Our study
demonstrated similar global resting strain rate to Liang et al.
(Tab. 1). However, our study was able to accurately
differentiate patients with previous myocardial infarction on
LGE imaging and demonstrate clear differences of strain
rate at rest in patients with/without previous myocardial
infarction (Tab. 2). A pre-clinical porcine study by Reant
et al. also demonstrated that flow reduction in the coronary
artery achieved by adenosine-induced myocardial
hyperaemia (flow reduction by 70%) adversely affected
myocardial deformation parameters (mainly longitudinal and
circumferential strain) at stress [
]. In a multi-centre study
of 102 patients who underwent concomitant dobutamine
stress echocardiography and coronary angiography,
longitudinal strain at peak stress demonstrated better diagnostic
accuracy than wall motion score [
]. In the same study,
a dobutamine stress GLS cut-off of –20% demonstrated
84% sensitivity and 87% specificity for significant CAD.
The optimum cut-off for stress GLS in our study was very
similar at –19.8%.
The sample size of this proof-of-concept study is small,
although large enough to detect statistically significant
differences on logistic regression analysis and thus
justifying larger studies to investigate this concept further. For
practical and conceptual reasons, we did not use
coronary stenosis on invasive angiography but perfusion
defects on myocardial perfusion CMR as the primary
]. Contemporary CMR pulse-sequences for
firstpass perfusion are highly accurate for the diagnosis of
significant ischaemia [
]. This work is
hypothesis-generating research and offers mechanistic insights which need
to be validated against the gold standard for
physiologically significant ischaemia, invasive FFR. Our results may
not be applicable to patients with infiltrative
cardiomyopathies (hypertrophic cardiomyopathy, cardiac
amyloidosis, sarcoidosis etc.), where stiffening of the left
ventricle may affect myocardial deformation [
]. Several papers
have demonstrated that the aforementioned infiltrative
cardiomyopathies lead to reduced GLS so that adenosine stress
GLS analysis may not be reliable [
]. Importantly, this
study also had a few technical limitations. Stress
myocardial deformation was only assessed in one plane, i. e. the
4-chamber cine. Strain rate imaging parameters derived by
FT suffer from low temporal resolution. Even though
FTderived strain analysis is very reliable for global assessment,
its reliability at regional level assessment is debatable ,
mainly because of intra-/inter-observer variability. Hence,
this was not done in the present study.
In this mechanistic study, at peak myocardial hyperaemic
stress, GLS is reduced in the presence of a myocardial
perfusion defect, most likely secondary to reduced endocardial
blood flow as a result of hyperaemia-induced redistribution
of transmural perfusion. Additionally, this study
demonstrates the feasibility of adenosine stress myocardial strain
CMR which may provide clinically relevant information
and justifies further larger studies to investigate the accuracy
of using CMR-FT-derived strain to predict the presence of
Funding British Heart Foundation (FS/10/62/28409)
Conflict of interest P. Garg, R. Aziz, T. Al Musa, D.P. Ripley, P. Haaf,
J.R.J. Foley, P.P. Swoboda, G.J. Fent, L.E. Dobson, J.P. Greenwood and
S. Plein declare that they have no competing interests.
Open Access This article is distributed under the terms of the
Creative Commons Attribution 4.0 International License (http://
creativecommons.org/licenses/by/4.0/), which permits unrestricted
use, distribution, and reproduction in any medium, provided you give
appropriate credit to the original author(s) and the source, provide a
link to the Creative Commons license, and indicate if changes were
1. Wolff SD , Schwitter J , Coulden R , et al. Myocardial first-pass perfusion magnetic resonance imaging: a multicenter dose-ranging study . Circulation . 2004 ; 110 : 732 - 7 . http://www.ncbi.nlm.nih.gov/ pubmed/15289374.
2. Pan J , Huang S , Lu Z , et al. Comparison of myocardial transmural perfusion gradient by magnetic resonance imaging to fractional flow reserve in patients with suspected coronary artery disease . Am J Cardiol . 2015 ; 115 : 1333 - 40 .
3. Radjenovic A , Biglands JD , Larghat A , et al. Estimates of systolic and diastolic myocardial blood flow by dynamic contrast-enhanced MRI . Magn Reson Med . 2010 ; 64 ( 6 ): 1696 - 703 . https://doi.org/10. 1002/mrm.22538.
4. Algranati D , Kassab GS , Lanir Y . Why is the subendocardium more vulnerable to ischemia? A new paradigm . Am J Physiol Heart Circ Physiol . 2011 ; 300 : H1090 - H100 .
5. Chiribiri A , Hautvast GLTF , Lockie T , et al. Assessment of coronary artery Stenosis severity and location: quantitative analysis of transmural perfusion gradients by high-resolution MRI versus FFR . JACC Cardiovasc Imaging . 2013 ; 6 : 600 - 9 .
6. Panaich S , Briasoulis A , Cardozo S , Afonso L. Incremental value of two dimensional speckle tracking echocardiography in the functional assessment and characterization of subclinical left ventricular dysfunction . Curr Cardiol Rev . 2016 ; 13 ( 1 ): 32 - 40 .
7. Swoboda P , McDiarmid AK , Erhayiem B , et al. The association between fibrosis and contractile dysfunction in hypertrophic cardiomyopathy assessed by cardiovascular magnetic resonance . Eur Heart J Cardiovasc Imaging . 2016 ; 17 ( Suppl 1 ): i1 - i80 . https://doi. org/10.1093/ehjci/jew093.
8. Pedrizzetti G , Claus P , Kilner PJ , et al. Principles of cardiovascular magnetic resonance feature tracking and echocardiographic speckle tracking for informed clinical use . J Cardiovasc Magn Reson . 2016 ; 18 : 51 . https://doi.org/10.1186/s12968-016-0269-7.
9. Schulz-Menger J , Bluemke DA , Bremerich J , et al. Standardized image interpretation and post processing in cardiovascular magnetic resonance: Society for Cardiovascular Magnetic Resonance (SCMR) board of trustees task force on standardized post processing . J Cardiovasc Magn Reson . 2013 ; 15 : 35 .
10. Cerqueira MD , Weissman NJ , Dilsizian V , et al. Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart. A statement for healthcare professionals from the Cardiac Imaging Committee of the Council on Clinical Cardiology of the American Heart Association . Circulation. 2002 ; 105 : 539 - 42 .
11. Fent GJ , Garg P , Foley JRJ , et al. The utility of global longitudinal strain in the identification of prior myocardial infarction in patients with preserved left ventricular ejection fraction . Int J Cardiovasc Imaging . 2017 ; https://doi.org/10.1007/s10554-017-1138-7.
12. Plein S , Kozerke S , Suerder D , et al. High spatial resolution myocardial perfusion cardiac magnetic resonance for the detection of coronary artery disease . Eur Heart J . 2008 ; 29 : 2148 - 55 .
13. Reimer KA , Jennings RB . The 'wavefront phenomenon' of myocardial ischemic cell death. II. Transmural progression of necrosis within the framework of ischemic bed size (myocardium at risk) and collateral flow . Lab Invest . 1979 ; 40 : 633 - 44 .
14. Greenbaum RA , Ho SY , Gibson DG , Becker AE , Anderson RH . Left ventricular fibre architecture in man . Heart . 1981 ; 45 : 248 - 63 .
15. Birkeland S , Westby J , Hessevik I , et al. Compensatory subendocardial hyperkinesis in the cat is abolished during coronary insufficiency outside an acutely ischaemic region . Cardiovasc Res . 1992 ; 26 : 285 - 91 .
16. Liang H-Y , Cauduro S , Pellikka P , et al. Usefulness of two-dimensional speckle strain for evaluation of left ventricular diastolic deformation in patients with coronary artery disease . Am J Cardiol . 2006 ; 98 : 1581 - 6 .
17. Reant P , Labrousse L , Lafitte S , et al. Experimental validation of circumferential, longitudinal, and radial 2-dimensional strain during dobutamine stress echocardiography in ischemic conditions . J Am Coll Cardiol . 2008 ; 51 : 149 - 57 .
18. Ng ACT , Sitges M , Pham PN , et al. Incremental value of 2-dimensional speckle tracking strain imaging to wall motion analysis for detection of coronary artery disease in patients undergoing dobutamine stress echocardiography . Am Heart J . 2009 ; 158 : 836 - 44 .
19. Chow BJW , Abraham A , Wells GA , et al. Diagnostic accuracy and impact of computed tomographic coronary angiography on utilization of invasive coronary angiography . Circ Cardiovasc Imaging . 2009 ; 2 : 16 - 23 .
20. Greenwood JP , Maredia N , Younger JF , et al. Cardiovascular magnetic resonance and single-photon emission computed tomography for diagnosis of coronary heart disease (CE-MARC): a prospective trial . Lancet . 2012 ; 379 : 453 - 60 .
21. Seward JB , Casaclang-verzosa G . Infiltrative cardiovascular diseases: cardiomyopathies that look alike . J Am Coll Cardiol . 2010 ; 55 : 1769 - 79 .
22. Afonso L , Kondur A , Simegn M , et al. Two-dimensional strain profiles in patients with physiological and pathological hypertrophy and preserved left ventricular systolic function : a comparative analyses . BMJ . 2012 ; 2 : 1 - 9 .
23. Kul S , Ozcelik HK , Uyarel H , et al. Diagnostic value of strain echocardiography, galectin-3, and tenascin-C levels for the identification of patients with pulmonary and cardiac sarcoidosis . Lung . 2014 ; 192 : 533 - 42 .