Diabetes as an independent predictor of left

ventricular longitudinal strain reduction at

rest and during dobutamine stress test in
patients with significant coronary artery
disease
Karina Wierzbowska-Drabik Ewa Trzos Małgorzata Kurpesa Tomasz Rechciński Dawid
Miśkowiec Urszula Cieślik-Guerra Barbara Uznańska-Loch Maria Sobczak Jarosław Damian
Kasprzak
European Heart Journal - Cardiovascular Imaging, jex315,
https://doi.org/10.1093/ehjci/jex315
Published:
09 December 2017
Article history

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Abstract
Aims

Diabetes (DM) is a strong cardiovascular risk factor modifying also the left ventricular (LV)
function that may be objectively assessed with echocardiographic strain analysis. Although
the impact of isolated DM on myocardial deformation has been already studied, few data
concern diabetics with coronary artery disease (CAD), especially in all stages of dobutamine
stress echocardiography (DSE). We compared LV systolic function during DSE in CAD with
and without DM using state-of-the art speckle-tracking quantification and assessed the impact
of DM on LV systolic strain.
Methods and results

DSE was performed in 250 patients with angina who afterwards had coronarography with
≥50% stenosis in the left main artery and ≥70% in other arteries considered as significant. In
this analysis, we included 127 patients with confirmed CAD: 42 with DM [DM(+); mean age
64 ± 9 years] and 85 patients without DM [DM(−); mean age 63 ± 9 years]. The severity of
CAD and LV ejection fraction (EF) were similar in both groups. Global and regional LV
peak systolic longitudinal strain (PSLS) revealed in all DSE phases lower values in DM(+)
group: 14.5 ± 3.6% vs. 17.4 ± 4.0% at rest; P = 0.0001, 13.8 ± 3.9% vs. 16.7 ± 4.0% at peak
stress; P = 0.0002, and 14.2 ± 3.1% vs. 15.5 ± 3.5% at recovery; P = 0.0432 for global
parameters, although dobutamine challenge did not enhance further resting differences. LV
EF, body surface area, and diabetes were independent predictors for strain in 16-variable
model (R2 = 0, 51, P < 0.001).

Conclusion

PSLS although diminished in both groups with CAD was lower in diabetics at all DSE
stages, and DM was an independent predictor of this impairment. However, the dobutamine
challenge did not deepen the resting differences, suggesting that the direct impact of coronary
stenoses effaces the influence of DM during DSE. The comparison with our previous data
revealed synergistic, detrimental effect of coexisting CAD and DM on myocardial strain.

dobutamine stress echocardiography , coronary artery disease , diabetes , speckle tracking ,

automated function imaging , systolic longitudinal strain
Topic:

 angina pectoris
 myocardium
 dobutamine
 coronary arteriosclerosis
 echocardiography
 diabetes mellitus
 left ventricle
 diabetes mellitus, type 2
 echocardiography, stress, dobutamine
 exercise stress test
 body surface area
 constriction, pathologic
 systole
 stress
 two-dimensional speckle tracking
 longitudinal strain

Issue Section:
Original Paper

Introduction
Diabetes mellitus (DM) accelerates atherosclerosis, doubles the risk of cardiovascular
complications, contributes to the development of diastolic heart failure, and worsens the
results of surgical treatment.1–3 Because the changes of heart function in DM may be initially
subtle and poorly detectable with conventional echocardiography, the introduction of novel
quantitative tools based on speckle-tracking analysis to assess myocardial deformation may
improve the understanding of cardiac mechanics. Global left ventricular (LV) strain was
proposed as a marker for diabetic cardiomyopathy, potentially more sensitive and precise
than parameters of diastolic function and easier for obtaining than coronary flow reserve in
distal left anterior descending artery (LAD).4,5 Moreover, the evaluation of longitudinal strain
during stress echocardiography seems to offer additional diagnostic value in DM without
significant coronary artery disease (CAD), revealing delayed recovery of peak systolic
longitudinal strain (PSLS) in diabetics.6 Nevertheless, the objectively measured, quantitative
influence of DM onto contractile myocardial function in subjects with confirmed CAD,
especially in the settings of dobutamine stress echocardiography (DSE), was not so far
adequately examined.

The aim of our study was to compare quantitative, inherent indices of the LV systolic
function during all stages of DSE (baseline, peak and recovery) in patients with significant
CAD and coexistent DM [DM (+) group] and with CAD but without DM [DM (−) group]
using automated function imaging (AFI), speckle tracking-based method available on board
of advanced echocardiographic systems. Additionally, we evaluated the impact of DM on LV
PSLS in multivariate analysis including 16 clinical and echocardiographic variables.

Methods
Study group and protocol

As we previously described in the literature,6,7 we examined 250 subjects with angina by

DSE with early atropine administration achieving 238 diagnostic tests (105 women, mean age
62 ± 90 years). The study flow chart is shown in Figure 1. All patients were in sinus rhythm
and had no significant valve disease (except for mild-to-moderate insufficiency) as well as
left bundle branch block conduction pattern. Exclusion criteria included contraindications to
dobutamine and atropine. Study group in this analysis involved 127 patients with confirmed
CAD: 42 with DM, diagnosed according to the standard criteria as type 2 of DM [DM (+)
group], mean age 64 ± 9 years, 12 women and 85 patients with CAD but without DM [DM
(−) group], mean age 63 ± 9, 25 women. All the included patients in this study were different
from the group described in Wierzbowska-Drabik et al.6,7 (where 111 patients without
significant CAD were analysed).

Figure 1

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Flow chart of the study patients examined by dobutamine stress echocardiography. CAD,
coronary artery disease; CT, computed tomography; Cx, circumflex artery; DM, diabetes
mellitus; DSE, dobutamine stress echocardiography.

Coronary arteries were evaluated by invasive coronary angiography or computed tomography

no later than 3 months after DSE. Significant stenosis was defined as narrowing ≥50% in the
left main coronary artery or ≥70% in other major arteries. All subjects gave written informed
consent, and the protocol was approved by Ethical Commission of Medical University of
Lodz.

Resting and stress echocardiography

Transthoracic echocardiography was performed with VIVID 7 Dimension (GE Vingmed

Ultrasound AS, Horten, Norway) using M4S probe in harmonic mode 2.0/4.3 MHz with
maximal frame per second (FPS) count available at necessary sector width, achieving on
average 82 ± 8 FPS. Echocardiographic measurements were performed following American
Society of Echocardiography/European Association of Echocardiography guidelines. LV EF
fraction was calculated according to the modified Simpson method from triplane mode
recorded with 3D probe.

LV contractility was assessed visually and classified for each segment as normokinesis
(Score 1), hypokinesis (Score 2), akinesis or dyskinesis (Score 3 or 4) using a 18-segment
model dividing each of 6 walls into 3 segments: basal, mid, and apical. Wall motion score
index (WMSI) was estimated as the sum of scores for all segments divided by the number of
segments. The worsening of contractility by at least one grade in two or more adjacent
segments was consistent with a positive DSE. Dobutamine was administered in the
intravenous infusion in doses of 10, 20, 30 and 40 µg/kg/min during 3-min stages, whereas
atropine was added in 0.5 mg fractional doses after the second stage of infusion, up to the
total dose of 2 mg. The infusion of dobutamine was stopped when heart rate limit, positive
test, or safety criteria were fulfilled.

The assessment of myocardial deformation

Standard echocardiographic views (three apical and three LV short axis) were stored at
baseline, peak, and recovery. Recovery images were recorded 10 min after dobutamine
stopping. The calculation of deformation was done using EchoPac 6.1.0 workstation (GE
Vingmed Ultrasound). Regional and global PSLS was calculated using AFI method. Briefly,
three points (two on basal and one on apical endocardium) were indicated in each apical
view, and computer-generated region of interest was optimized and approved by the operator.
Peak longitudinal deformation achieved for any segment before the aortic valve closure
(AVC) was recorded as PSLS. AVC was defined with the Doppler recording. The rounded
segmental values of PSLS were displayed as a polar map with additional calculation of the
averaged (from 6 segments) and global (from 18 segments) parameters. For each LV
segment, the value of PSLS was measured at baseline, peak, and recovery. Aiming at the
simplification of analysis we chose the mid segments of lateral, inferior wall and anterior
septum as marker, sentinel segments for the regions supplied by the circumflex (Cx), right
coronary artery (RCA) and LAD, respectively.

Statistical analysis

Statistical analysis was performed using MedCalc version 12.1.4. (Frank Schoonjans,
Belgium). Continuous variables were expressed as means and standard deviations. Mean
values were compared with the Student’s t test. The χ2 test was used to test the dichotomous
variables distribution. Correlations were assessed using Pearson and Spearman coefficients
for continuous and categorical variables, respectively, and multivariate analysis by multiple
regression was performed. The values of P < 0.05 were considered statistically significant.
Data for interobserver and intraobserver variability of AFI analysis before and during DSE
were calculated as coefficients of variation in randomly selected subgroups and published in
former articles.7,8 Briefly, interobserver variability (coefficient of variance) calculated for
segmental longitudinal strain was 8.7% and 16%, respectively, for AFI method at baseline
and peak stage of DSE.

Results
The compared groups did not differ according to age and gender, as well as the prevalence of
hypertension, smoking, and hypercholesterolaemia, although DM (+) patients had
significantly higher body mass and waist circumference. Similarily, blood pressure, heart
rate, history of myocardial infarction [45% in DM (+) group and 49% in DM (−) group,
P = ns], and medical treatment of CAD (beyond diabetes medications) were also similar
(Table 1). Moreover, both groups presented similar mean LV EF and WMSI (see Table 2) as
well as comparable severity and localization of CAD lesions (Table 3).

Table 1

Comparison of demographics, risk factors, and treatment between DM (+) and DM (−)
groups

DM (+) DM (−)
Parameters P-value
n = 42 n = 85
Age (years), mean ± SD 64 ± 9 63 ± 8 ns
Gender (numbers F/M) 12/30 25/60 ns
Height (cm), mean ± SD 169 ± 8 168 ± 9 ns
Body mass (kg), mean ± SD 87.7 ± 16.6 80.0 ± 14.8 0.0091
Body mass index (kg/m2), mean ± SD 30.7 ± 5.7 28 ± 3.9 0.0022
Waist circumference (cm), mean ± SD 103.4 ± 15.8 96.1 ± 14.2 0.0097
Body surface area (m2), mean ± SD 2.02 ± 0.2 1.92 ± 0.2 0.0081
Blood pressure systolic (mmHg), mean ± SD 132 ± 17 129 ± 19 ns
Blood pressure diastolic (mmHg), mean ± SD 73 ± 9 71 ± 11 ns
Heart rate at baseline (bpm), mean ± SD 65 ± 7 67 ± 10 ns
Obesity BMI ≥30 kg/m2, n (%) 16 (38) 26 (31) ns
Hypertension, n (%) 41 (98) 79 (93) ns
Smoking, n (%) 32 (76) 52 (61) ns
Hypercholesterolaemia, n (%) 42 (100) 76 (89) ns
Hypertriglicerydaemia, n (%) 39 (93) 49 (58) 0.0001
Total cholesterol, mean ± SD 193 ± 46 187 ± 46 ns
LDL cholesterol, mean ± SD 111 ± 37 108 ± 42 ns
HDL cholesterol, mean ± SD 49 ± 18 52 ± 21 ns
Triglycerides, mean ± SD 183 ± 124 138 ± 90 0.0214
Family history of CAD, n (%) 8 (19) 14 (16) ns
History of myocardial infarction 19 (45) 42 (49) ns
 DM (+) DM (−)
Parameters P-value
n = 42 n = 85
Typical angina 29 (69) 66 (78)
ns
Non-typical angina 13 (31) 19 (22)
Acetylsalicylic acid, n (%) 42 (100) 83 (98) ns
Clopidogrel, n (%) 26 (62) 39 (46) ns
Beta-blockers, n (%) 38 (90) 76 (89) ns
Angiotensin-converting enzyme inhibitor, n (%) 41 (98) 74 (87) ns
Statin, n (%) 42 (100) 82 (96) ns
Long-acting nitrates, n (%) 30 (71) 64 (75) ns

CAD, coronary artery disease; DM, diabetes; n, number of subjects.

Table 2

Comparison of baseline echocardiographic parameters between DM (+) and DM (−) groups

DM (+) DM (−)
Parameters P-value
n = 42 n = 85
LVd (mm) 47.9 ± 4.8 47.3 ± 5.1 ns
LVd index (mm/m2) 23.9 ± 3.1 24.8 ± 3.1 ns
LVs (mm) 34.2 ± 5.0 33.5 ± 6.1 ns
LVs index (mm/m2) 17.1 ± 3.1 17.5 ± 3.2 ns
PWd (mm) 12.3 ± 1.3 11.3 ± 1.1 <0.0001
PWd index (mm/m2) 6.1 ± 0.8 5.9 ± 0.7 ns
PWs (mm) 15.1 ± 1.7 14.1 ± 1.6 <0.0015
PWs index (mm/m2) 7.5 ± 1.0 7.4 ± 0.9 ns
IVSd (mm) 12.9 ± 1.6 11.9 ± 1.5 0.0007
IVSd index (mm/m2) 6.4 ± 0.9 6.2 ± 0.8 ns
IVSs (mm) 15.7 ± 1.7 14.8 ± 1.6 0.0041
IVSs index (mm/m2) 7.8 ± 1.0 7.7 ± 1.0 ns
Ao (mm) 33.1 ± 3.2 32.9 ± 3.6 ns
Ao index (mm/m2) 16.5 ± 1.9 17.3 ± 1.9 0.0274
LA (mm) 42.4 ± 2.9 40.9 ± 3.7 0.0231
LA index (mm/m2) 21.1 ± 2.2 21.4 ± 2.3 ns
RV (mm) 26.4 ± 2.0 26.4 ± 2.1 ns
RV index (mm/m2) 13.2 ± 1.4 13.8 ± 1.5 0.0321
E/A 0.7 ± −0.2 0.9 ± 0.5 0.014
LV mass (g) 277 ± 57 244 ± 67 0.0071
LV mass index (g/m2) 137 ± 27 126 ± 30 0.0468
EF baseline (%) 53 ± 7 54 ± 8 ns
WMSI at baseline 1.15 ± 0.2 1.17 ± 0.24 ns
 DM (+) DM (−)
Parameters P-value
n = 42 n = 85
S′ lat at baseline (cm/s) 7.7 ± 1.8 8.5 ± 2.5 ns
E′ lat at baseline (cm/s) 9.1 ± 3.1 9.6 ± 2.8 ns

Indexes were calculated by body surface area. Values were expressed as mean ± SD.

Ao, aortic dimension; DM, diabetes mellitus; E′ lat, peak early diastolic velocity of lateral
part of mitral annulus; E, peak velocity of mitral inflow early phase; E/A, ratio of early to
atrial mitral inflow peak velocity; EF, left ventricular ejection fraction; IVSd, end-diastolic
left ventricular septum thickness; IVSs, end-systolic left ventricular septum thickness; LA,
left atrial dimension; LV mass, left ventricular mass; LV mass index, left ventricular mass
index; LVd, left ventricular end-diastolic dimension; LVs, left ventricular end-systolic
dimension; n, number of subjects; PWd, end-diastolic left ventricular posterior wall
thickness; PWs, end-systolic left ventricular posterior wall thickness; RV, right ventricular
end-diastolic dimension; S′ lat, peak systolic velocity of lateral part of mitral annulus; WMSI,
wall motion score index.

Table 3

The comparison of CAD advancement and localization between groups with and without DM

DM (+) DM (−)
Symptom/parameters P-value
n = 42 n = 85
Three-vessel disease, n (%) 12 (29) 14 (16) ns
Two-vessel disease, n (%) 10 (24) 28 (33) ns
One-vessel disease, n (%) 20 (48) 43 (51) ns
LMCA stenosis >50% 6 (14) 6 (7) ns
LAD stenosis >70% 21 (50) 49 (58) ns
Cx stenosis >70% 21 (50) 42 (49) ns
RCA stenosis >70% 23 (55) 42 (49) ns
SYNTAX score (n 33/79), mean ± SD 17.3 ± 28.3 12.5 ± 8.5 ns
History of CABG 1 (2.4) 1 (1.2) ns
Number of patent/stenosed grafts, n (%) 3 (75)/1(25) 1 (100)/0(0) ns

Diabetics had higher body mass index (BMI; 30.7 ± 5.7 vs. 28 ± 3.9 in controls, P = 0.0022)
and had more often triglyceridaemia (see Table 1). Patients with CAD and DM had
comparable standard echocardiograms except for higher LV mass and LV mass index
(LVMI; 137 ± 27 g/m2 vs. 126 ± 30 g/m2, P = 0.0468, for mass index) as well as thicker LV
walls and larger left atrial diameter (significance was lost after indexing for BSA; see Table
2). We did not found any correlation between LVMI and PSLS in patients with diabetes
(r = 0.065, P = 0.68; r = 0.187, P = 0.24; r = 0.04, P = 0.81, respectively) for baseline, peak,
and recovery of DSE. In contrast, we observed the significant correlation between LVMI and
PSLS in group without DM, which was confirmed in all stages of DSE (r = 0.37, P = 0.0004;
r = 0.34, P = 0.013; r = 0.43, P = 0.0001, respectively) for baseline, peak, and recovery.
Severity of CAD was similar in both groups (Table 3) with comparable prevalence of
significant stenosis (>70%) in each of the major epicardial coronary artery or its significant
branch (diagonal arteries of diameter >2 mm were ascribed to LAD, marginal to Cx and
posterior descending and posterolateral to RCA). SYNTAX score did not differ between DM
(+) and DM (−) patients. Only two patients in the studied group had previous coronary artery
bypass grafting (CABG). One patient belonged into DM (+) group and presented patent left
interior mammary artery (LIMA) and two venous grafts, from which one venous graft
(supplying RCA) had 95% stenosis. The other patient belonged to DM (−) group and had
only one arterial graft—patent LIMA to LAD. Because of very small number, the proportion
of previous CABG and graft patency did not differ significantly between the compared
subgroups (see Table 3).

During DSE, standard echocardiographic parameters did not differ between DM (+) and DM
(−) groups. The percentage of positive DSE test (assessed visually) exceeded 80% in both
groups with chest pain prevalence and electrocardiographic (ECG) changes recorded in about
60%. Peak stress values of EF, WMSI, heart rate, and blood pressure were also similar as
well as the percentage of contractility impairment in myocardial regions supplied by
respective coronary arteries (Table 4).

Table 4

The comparison of the prevalence of chest pain, ECG changes, WMSI, and contractility
impairments between group with and without DM during DSE

DM (+) DM (−) P-
Symptom/parameters
n = 42 n = 85 value
Chest pain during DSE, n (%) 24 (57) 51 (60) ns
ECG ischemic changes at peak DSE, n (%) 26 (62) 49 (58) ns
1, 3 ± 0,
WMSI at peak, mean ± SD 1.3 ± 0.21 ns
24
0.13 ± 0,
Delta WMSI (peak–baseline), mean ± SD 0.15 ± 0.14 ns
13
Positive DSE test, n (%) 37 (88) 72 (85) ns
Systolic blood pressure at peak stage (mmHg), mean ± SD 145 ± 28 142 ± 26 ns
Diastolic blood pressure at peak stage (mmHg), mean ± SD 76 ± 11 75 ± 12 ns
Atropine mean dose (mg), mean ± SD 1.08 ± 0.53 0.96 ± 0.5 ns
Heart rate at peak stage (bpm), mean ± SD 138 ± 12 138 ± 16 ns
Heart rate at recovery (bpm), mean ± SD 92 ± 13 89 ± 12 ns
EF at peak DSE (%), mean ± SD 54 ± 7 55 ± 10 ns
Induced contractility impairment in the region of LAD
11 (26) 22 (26) ns
(number of subjects), n (%)
Induced contractility impairment in the region of Cx
21 (50) 38 (45) ns
(number of subjects), n (%)
Induced contractility impairment in the region of RCA
22 (52) 37 (44) ns
(number of subjects), n (%)
Cx, circumflex artery; DSE, dobutamine stress echocardiography; ECG, electrocardiogram;
LAD, left anterior descending artery; n, number of subjects; RCA, right coronary artery;
WMSI, wall motion score index.

Feasibility of longitudinal strain assessment with the standard 2D speckle-tracking

echocardiography with and without the use of AFI was analysed for regional and global data
and published in an earlier article,7 encompassing data from 238 patients including presently
analysed 127 subjects with CAD. Global LV PSLS correlated very well for both methods
(r = 0.90 at baseline and r = 0.86 at peak stage of DSE), but AFI analysis (used in this study)
was less time-consuming (mean time for obtaining regional, averaged, and global data for LV
in AFI was 168 ± 28 s vs. 367 ± 39 s by classical curves analysis with STE) and less operator
dependent with interobserver variability of 8.7% and 16% for baseline at peak stage,
respectively. Despite the inclusion of only patients with feasible visual assessment of all LV
segments in our study, we still excluded some segments from speckle-tracking analysis
because of suboptimal tracking quality. The respective percentage of excluded segments were
significantly higher at peak stage (1.07%) than at rest (0.42%, P = 0.0007).

In contrast to standard echocardiographic parameters, all assessed global, average, and

segmental PSLS measurements had lower absolute values in patients with CAD and DM at
all stages of DSE. In the majority of comparisons, observed differences were statistically
significant (Table 5), e.g. for global strain (averaged from 18 LV segments) measured at
baseline (14.5 ± 3.6% vs. 17.4 ± 4.0, P = 0.0001), peak (13.8 ± 3.9% vs. 16.7 ± 4.0%,
P = 0.0002), and recovery (14.2 ± 3.1% vs. 15.5 ± 3.5%, P = 0.04) and for averaged values
describing respective echocardiographic views (six segments from three-chamber, two-
chamber and four-chamber views) measured at baseline as well as for segmental values
(chosen from mid LV level as representative for Cx, RCA, and LAD supply) measured at
baseline. At peak DSE stage and at recovery, some comparisons, encompassing less number
of segments, did not reach statistical significance (Figure 2).

Table 5

Comparison of longitudinal peak systolic strain measured by AFI method between groups
with and without DM at baseline, peak, and during recovery phase of DSE (absolute values,
without minus)

DM (+) DM (−)
Parameters P-value
n = 42 n = 85
Global PSLS at baseline 14.5 ± 3.6 17.4 ± 4.0 0.0001
Global PSLS at peak 13.8 ± 3.9 16.7 ± 4.0 0.0002
Global PSLS at recovery 14.2 ± 3.1 15.5 ± 3.5 0.0432
Averaged 3ch PSLS at baseline 15.1 ± 4.3 17.6 ± 4.6 0.0039
Averaged 4 ch PSLS at baseline 14.4 ± 4.4 16.8 ± 4.1 0.003
Averaged 2 ch PSLS at baseline 14.5 ± 3.6 17.9 ± 4.3 <0.0001
Averaged 3ch PSLS at peak 14.2 ± 5.0 17.0 ± 4.7 0.0024
Averaged 4 ch PSLS at peak 14.6 ± 4.8 16.4 ± 5.4 ns
Averaged 2 ch PSLS at peak 13.0 ± 4.6 16.4 ± 4.8 0.0002
Averaged 3ch PSLS at recovery 14.3 ± 4.0 15.6 ± 4.2 ns
 DM (+) DM (−)
Parameters P-value
n = 42 n = 85
Averaged 4 ch PSLS at recovery 13.9 ± 3.8 15.5 ± 3.8 0.0274
Averaged 2 ch PSLS at recovery 13.9 ± 3.6 15.6 ± 3.6 0.0136
Mid lateral PSLS at baseline 9.8 ± 7.4 13.4 ± 7.0 0.0085
Mid inferior PSLS at baseline 16.5 ± 4.4 19.6 ± 5.7 0.0024
Mid anteroseptal PSLS at baseline 16.8 ± 5.7 19.7 ± 4.5 0.0022
Mid lateral PSLS at peak 9.1 ± 6.3 11.7 ± 9.7 ns
Mid inferior PSLS at peak 15.4 ± 6.4 18.1 ± 5.5 0.0151
Mid anteroseptal PSLS at peak 16.1 ± 6.6 18.2 ± 6.7 ns
Mid lateral PSLS at recovery 10.2 ± 6.5 13.1 ± 5.5 0.0096
Mid inferior PSLS at recovery 14.9 ± 5.0 17.1 ± 5.0 0.0213
Mid anteroseptal PSLS at recovery 15.3 ± 6.2 17.2 ± 5.1 ns

Global—mean value from 18 segments, 2ch, 3ch, and 4ch—parameters measured as mean
values from six segments in respective apical views, mid lateral, mid inferior, mid
anteroseptal—parameters measured in respective segments of left ventricle considered
‘marker segments’ for Cx, RCA and LAD supply region. Values were expressed as
mean ± SD.

2ch, apical two-chamber view; 3ch, apical three-chamber view; 4ch, apical four-chamber
view; CAD, coronary artery disease; DM, diabetes mellitus; PSLS, peak systolic longitudinal
strain; n, number of subjects.

Figure 2

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Comparison of global and regional PSLS, recorded during baseline, peak, and recovery stage
of DSE in patients with CAD and DM (red bars) and CAD without DM (green bars).
Absolute strain values at baseline and majority at the peak and during recovery are lower in
diabetics. The coexistence of diabetes significantly impairs left ventricular systolic function
at rest, during, and after stress echocardiography in patients with coronary artery disease.

As far as the comparison of observed changes of PSLS during DSE are concerned for global
strain, it reached the mean value of 1.8 ± 2.3% in DM (−) group and 1.2 ± 2.6% in DM (+)
patients for the drop of absolute PSLS value between baseline and recovery and they did not
reveal statistically significant differences between groups. Figure 3 shows a typical example
of positive DSE tests in CAD patients with and without DM, illustrating deeper impairment
of PSLS in all stages of DSE in patient with coexisting DM.

Figure 3

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A representative example of two positive DSE tests (posteroinferior ischaemia in patient with
CAD and DM vs. posterolateral ischaemia in patient without DM). Absolute values of PSLS
in patient with CAD and DM are lower at all analysed stages (upper panel).

We found that in diabetics included in our DM (+) group, LV hypertrophy (LVMI) does not
significantly affect the PSLS values at any of DSE stages. Moreover, in both subgroups of
diabetics (stratified according to LVMI with average value found in the group accepted as
cut-off), PSLS was impaired (see Table 6, upper part). In contrast, in patients without
diabetes, PSLS was significantly decreased in subgroup with higher values of LVMI at
baseline and recovery stages of DSE (subgroups divided according to the average value in
non-diabetics, bottom lines of Table 6).

Table 6

Separate comparison of PSLS recorded during all stages of DSE according to LVMI in
patients with and without diabetes

DM (+) and LVMI <137 g/m2 DM (+) and LVMI ≥137 g/m2 P-
Parameters
(n = 16) (n = 26) value
PSLS
14.1 ± 4.3 15.0 ± 3.2 ns
baseline
PSLS peak 14.1 ± 4.6 13.6 ± 3.6 ns
PSLS
13.7 ± 3.3 14.6 ± 3.1 ns
recovery
DM (−) and LVMI <126 g/m2 DM (−) and LVMI ≥126 g/m2 P-
Parameters
(n = 45) (n = 40) value
PSLS
18.3 ± 3.6 16.2 ± 4.1 0.0144
baseline
PSLS peak 17.4 ± 3.6 15.7 ± 4.3 ns
PSLS
16.4 ± 3.0 14.4 ± 3.6 0.0068
recovery

In contrast to non-diabetics group in patients with DM, the increase of LVMI did not seem to
have further impact on PSLS. Values were expressed as mean ± SD.

DM, diabetes mellitus; LVMI, left ventricular mass index; n, number of subjects; PSLS, peak
systolic longitudinal strain.

We found that in patients with CAD and without or with only mild LV hypertrophy (for
LVMI < 126 g/m2), the presence of DM was still related with decreased PSLS values
measured at all stages of DSE. This finding was consistent with the relationships observed for
the whole group not stratified according to the LVMI (compare data in Tables 5 and 7).
Nevertheless, in the settings of moderate or severe LV hypertrophy (LVMI ≥ 126 g/m2 and
<150 g/m2 or LVMI ≥ 150 g/m2), the decrease of strain values in diabetics when compared
with respective non-diabetic group with LV hypertrophy lost its statistical significance and
the additional impact of DM on PSLS was not then detectable (see Table 7).

Table 7
Comparison of PSLS between diabetics and non-diabetics stratified according to LVMI

DM (+) and LVMI <126 g/m2 DM (−) and LVMI <126 g/m2 P-
Parameters
(n = 14) (n = 45) value
PSLS
14.1 ± 4.0 18.3 ± 3.6 0.0005
baseline
PSLS peak 14.0 ± 4.5 17.4 ± 3.6 0.0066
PSLS
13.9 ± 3.2 16.4 ± 3.0 0.0143
recovery
DM (+) and LVMI ≥126 and DM (−) and LVMI ≥126 and P-
Parameters
<150 g/m2 (n = 16) <150 g/m2 (n = 22) value
PSLS
15.2 ± 3.4 17.4 ± 4.0 ns
baseline
PSLS peak 14.8 ± 4.0 17.1 ± 4.5 ns
PSLS
14.9 ± 3.9 15.6 ± 3.2 ns
recovery
DM (+) and LVMI ≥150 g/m2 DM (−) and LVMI ≥150 g/m2 P-
Parameter
(n = 12) (n = 18) value
PSLS
14.4 ± 3.6 14.9 ± 3.9 ns
baseline
PSLS peak 12.4 ± 2.9 14.1 ± 3.5 ns
PSLS
13.7 ± 2.1 13.2 ± 3.7 ns
recovery

The data show that in patients without or with only mild hypertrophy the presence of DM
decreases the absolute value of longitudinal strain at all stages of DSE. Contrary this impact
is abolished in patients with severe or moderate hypertrophy. Values were expressed as
mean ± SD.

DM, diabetes mellitus; LVMI, left ventricular mass index; n, number of subjects; PSLS, peak
systolic longitudinal strain.

In the whole studied group, PSLS showed significant relationships with body mass, BMI, and
waist circumference as well as diabetes for all stages of DSE in univariate analysis (see Table
8). In multivariate analysis including 16-variable LV EF, body surface area, and diabetes
were independent predictors of PSLS in model with coefficient of determination (R2 = 0.51,
P < 0.001).

Table 8

Correlations between demographic and clinical factors and PSLS in subsequent stages of
DSE in univariate analysis

Parameters PSLS baseline PSLS peak PSLS recovery

Body mass r = 0.35; P < 0.0001 r = 0.25; P = 0.0046 r = 0.24; P = 0.0102
Body mass index r = 0.33; P = 0.0001 r = 0.30; P = 0.0006 r = 0.27; P = 0.0029
 Parameters PSLS baseline PSLS peak PSLS recovery
Waist circumference r = 0.36; P < 0.0001 r = 0.35; P = 0.0001 r = 0.32; P = 0.0004
Body height r = 0.18; P = 0.044 ns ns
Diabetes rho = 0.34; P = 0.0001 rho = 0.31; P = 0.0004 rho = 0.23; P = 0.013
Hypertension ns ns ns
Hypertriglyceridaemia ns rho = 0.29; P = 0.0009 ns
Smoking ns ns ns

DSE, dobutamine stress echocardiography; PSLS, peak systolic longitudinal strain; r,

Pearson correlation coefficient; rho, Spearman correlation coefficient.

Finally, we compared the data from this analysis with the second part of our group which we
previously described (Wierzbowska-Drabik et al.6) and which had no CAD and was divided
according to DM presence. This comparison displayed a similar impairment of strain in
patients with the presence of one factor DM (+) or CAD (+) and the deepest impairment of
LV function when both factors were present. Interestingly, this relationship was observed at
all DSE stages, (see Figure 4 displaying data from Wierzbowska-Drabik et al.6 and from this
study).

Figure 4

View largeDownload slide

The comparison of mean absolute values of global PSLS at different stages of DSE according
to the presence of CAD, DM, or both these factors. The data illustrate the equivalent impact
of isolated DM and CAD without diabetes on LV myocardial strain and the synergistic
influence of the coexistence of both these factors. The number of patients included in figure
groups: 1. CAD (−) DM (−), n = 85; 2. CAD (−) DM (+), n = 25 (asterisk indicates data from
the study by Wierzbowska-Drabik et al.6); 3. CAD (+) DM (−), n = 85; 4. CAD (+) DM (+),
n = 42 (data from this study). In the majority of comparisons, the significantly lower strain
values were observed in CAD patients when compared with their counterparts without CAD.
Nevertheless, this significance was limited to trend only at peak stage of DSE in subgroup
without DM and was totally effaced at recovery stage in subgroup with DM. The last finding
may suggest the delayed recovery and even further impairment of contractile left ventricular
function in patients with DM submitted to DSE.

Moreover, the comparison of PSLS limited to the subgroup with negative visually assessed
DSE results indicated on potential utility of longitudinal strain for differentiation between
true-negative and false-negative DSE examinations (see Figure 5). The data show that
patients with CAD with assessed visually negative DSE presents in the majority of
comparisons lower absolute PSLS value than their true negative counterparts. As far as our
data are concerned, the statistical significance was achieved only in non-diabetics during
recovery phase, but it may depend from very limited number of false-negative subgroup.

Figure 5

View largeDownload slide

The comparison of mean absolute values of global PSLS at different stages of DSE according
to the presence of CAD, DM, or both these factors limited to the patients with negative
results of visually assessed DSE (negative tests according to wall mottion analysis). The data
illustrate the potential of global longitudinal strain for the detection of systolic function
impairment in patients with CAD which was not detected during conventional visually
assessed DSE. Despite limited number of subjects in groups with false-negative DSE, the
global PSLS was significantly diminished in CAD (+) group in patients without DM as
measured during recovery stage. Moreover, all but one (unexpectedly concerning peak DSE
stage) numeric values of GLS in CAD (+) were lower than the respective measurements for
CAD (−) patients. The number of patients in all figure groups: 1. CAD (−) DM (−), n = 61; 2.
CAD (−) DM (+), n = 22 (asterisk indicates data from study by Wierzbowska-Drabik et al.6);
3. CAD (+) DM (−), n = 13; and 4. CAD (+) DM (+), n = 4 (data from this study).

Discussion
Our study documents decreased longitudinal function of LV in CAD patients with coexisting
type 2 DM in comparison with CAD without diabetes at rest, during, and after dobutamine
stress test, which, according to our knowledge, was not published so far. Importantly, this
global and regional impairment could be detected only with deformation analysis, because
EF, systolic velocity of mitral annulus motion or WMSI did not differ between the compared
groups. Moreover, our groups were comparable according to diastolic function parameters:
lateral mitral annular velocity and left atrial volume index, although LV mass index was
higher in DM (+).

Nevertheless, we did not find significant correlation between LVMI and PSLS in patients
with diabetes, which allowed us to the assumption that observed lower results of PSLS in DM
(+) group does not depend on higher mean LVMI in our diabetic subjects. On the other hand,
in further subgroup analysis, lower values of PSLS in diabetics were still significant for all
DSE stages in patients with the LVMI < 126 g/m2 so showing no or mild hypertrophy of LV
walls, whereas in patients with moderate and severe hypertrophy, the additional impact of
DM was not expressed (Table 7). However, these related to subgroups analysis pilot data are
limited by small number of included subjects so they should be proved in further studies.

Similar advancement (expressed as SYNTAX score) and localization of significant lesions in

coronary arteries allow for assumption that the presence of diabetes and strictly related
hypertriglyceridaemia are the main determinants of the observed PSLS impairment.
Interestingly, in comparison with our previously published analysis in which we observed
diminished PSLS in diabetics patients without CAD mainly during recovery stage of DSE, in
this study, the detrimental impact of DM on cardiac function seems to be stronger and overt
also at rest and peak stage of DSE.6

Moreover, counter-intuitive at first look observation that the dobutamine challenge did not
deepen the differences observed at rest was accomplished. It may suggest that the direct
impact of the significant coronary stenoses effaces the more subtle influence of DM on
systolic myocardial function during DSE or that the assessment of PSLS is more difficult at
higher heart rates (reaching in our study an average value of 138 bpm). The increase of
technical challenge at peak stage of DSE was not only suspected but also documented as the
deacresed feasibility (more segments excluded from the analysis) and nearly twice increased
interobserver variability between baseline and peak stage of test (from 8.7% to 16%).
Nevertheless, these technical limitations may not solely explain the observed relationships
because the intrinsic features of strain values diminishing during very rapid heart rates (HRs)
and shortened cardiac cycles may limit diagnostic utility of the recordings during high-level
tachycardia. Currently, there are still few published data concerning strain analysis when the
HR is close to 140 bpm in groups including >100 patients with confirmed CAD. The typical
reaction of PSLS at lower level of induced HR is the increase of longitudinal deformation,
whereas during further increase of tachycardia the deformation values decrease, as it was in
our group. This biphasic pattern of strain changes increasing at low stress but constant or
decreasing as the HR further increases was described in earlier and more recent studies with
DSE or exercise test in healthy children.9–11 These observations, as well as recent studies
documenting the lack of diagnostic benefit of strain assessment during peak stage of exercise
test in such settings as aortic stenosis or better documented values of resting then exercise or
dobutamine-related deformation in CAD diagnosis, may additionally prompt to focusing on
recovery stage when the HR is close to baseline but some detrimental effects may be still
present at least in the aspect of ischaemia detection.12–14

The diagnostic potential of PSLS assessment during DSE for myocardial ischaemia detection
was in our study observed in the combined analysis of data from patients with and without
CAD showing negative DSE test according to visual evaluation (Figure 5). Non-diabetics
patients with false-negative visual test presented significantly lower PSLS during recovery
phase of DSE than ‘true-negative’ subjects (15.1 ± 3.1% vs. 17.6 ± 3.1%, P = 0.0102).

Strain analysis in patients with coexisting CAD and DM in comparison with patients without
DM and similar severity of CAD, especially during all stages of stress test, is unique in the
literature. Moreover, published data on resting assessment of myocardial deformation raise
numerous controversies. Loncarevic et al.15 in group of 70 patients with type 2 DM without
hypertension and CAD reported impaired global longitudinal strain and early diastolic strain
rate in comparison with healthy group. The association of DM with arterial hypertension
(HA) or CAD caused further decrease in the absolute values of longitudinal strain from
18.71 ± 1.86% in controls, through 17.36 ± 1.8% in isolated DM to 16.31 ± 2.79% in DM
with HA, and 16.26 ± 2.84% in DM and CAD. Similarly in our data, patients without CAD
and DM [CAD (−)/DM (−)] showed the highest absolute values of global PSLS (e.g.
−18.7 ± 3.3% at rest), patients with one factor DM (+) or CAD (+) showed lowered and very
similar values of strain, reflecting the equivalent impact of isolated DM or CAD without DM
on myocardial function and at last patients with CAD and DM showed the deepest
impairment of LV function. Interestingly this relationship was observed at all DSE stages
(Figure 4, data from Wierzbowska-Drabik et al.6 and this study).

In the study of Enomoto et al.,16 diabetics in comparison with healthy controls showed not
only lowered longitudinal and circumferential strain but also area strain obtained with 3D
speckle-tracking method (12.0 ± 3.0% vs. 16.2 ± 1.9%, 27.7 ± 7.1% vs. 32.2 ± 5.7%,
37.6 ± 7.6% vs. 44.0 ± 6.2%, respectively; P < 0.001), and these changes correlated with
severity of microvascular dysfunction measured as the advancement of nephropathy,
neuropathy, and retinopathy. In another study, Bonapace et al.17 observed in a 2-year follow-
up that impaired longitudinal strain in patients with DM had predictive value for new onset of
atrial fibrillation.

In multivariate analysis in our study, the presence of type 2 DM, value of EF, and body
surface area were independent predictors of PSLS. These results underlined the utility of
strain analysis in the detection of functional LV changes related with DM and potentially its
advancement and treatment. This seems especially important considering that some glucose-
lowering medications were associated with an increased risk of developing heart failure.18

The following observations offer in our opinion significant novelty and belong to the
potential clinical implications of our study:

 the presence of DM impairs global (and regional) LV myocardial function, which

may be observed also in patients with coexisting CAD. The significant differences
were observed at rest as well as during DSE and recovery when compared with CAD
without DM.
 our data from this and previous studies provide some reference values of PSLS for
patients who are often examined with stress echocardiography and may be
categorized according to CAD and DM presence. Interestingly, the impact of isolated
DM or CAD on PSLS seems to be similar, whereas the coexistence of CAD and DM
exerts the strongest influence on myocardial contractility at all stages of DSE (Table
4).
 the observation that dobutamine challenge does not increase the resting difference of
PSLS between patients with and without DM and CAD have hypothesis-generating
character and should be confirmed in further, larger studies. Hypothetically, it may be
related to the predominant effect of significant stenoses of coronary arteries that were
present in both groups and effaced the impact of DM during stress test. Analogously,
the presence of CAD reversed the protective effect of female sex on some diastolic
function parameters and the presence of DM abolished the prognostic significance of
anti-ischaemic therapy continued in the time of stress echocardiography in some of
our previous studies.19,20

Our study is one of the first attempting at detailed characteristic of LV function in diabetics in
the settings of coexisting CAD and stress challenge. Although focused on longitudinal strain,
we tried to conduct comprehensive assessment during DSE, including also less examined
recovery stage. Because of variability of PSLS values related to localization in the LV region,
we looked also at segmental and regional functions and did separate analysis concerning
middle LV segments. Our results confirm that PSLS can be considered as an emerging tool in
the assessment of diabetic myocardial dysfunction.

Limitations

Small number of examined diabetics (42 subjects) and the lack of detailed biochemical
characteristics represent the main limitations of our study which precludes also the potential
subanalyses related to severity of DM. Despite similar age, gender, and basically assessed
CAD advancement, the DM patients exhibited higher body mass, BMI, waist circumference,
body surface area, and LVMI, which might influence the obtained PSLS results.

According to clinically oriented guidelines,21 we chose to focus on longitudinal strain for

practical aspects of easy, on-system automated imaging method, which can serve as a
supplement to routine DSE analysis. Aiming at different stages of DSE, global and regional
analyses, and integration of relevant data from previous part of study (four different groups of
patients divided according to CAD and DM presence), we limited the analyses to the most
popular parameter PSLS without including the postsystolic shortening.
Similarly, the additional long-term analysis of prognostic significance of reduced global
PSLS at rest and during DSE may potentially increase the clinical utility of our observations.
Finally, our data were derived from a single vendor of echocardiographic equipment, and the
studied patients were recruited from a single cardiology department.

Conclusions
Longitudinal LV deformation is more impaired in patients with CAD and DM in comparison
with their counterparts with similar extent of coronary atherosclerosis but without DM. This
finding was detectable not only at rest but also at peak and recovery stage of DSE and
concerned not only on global parameters but also on individual LV segments. DM is an
independent predictor of baseline PSLS, which suggests a specific impact on the
development of LV dysfunction and, subsequently, heart failure. Moreover, the comparison
with our previous data suggest that the severity of detrimental effect of isolated DM and
CAD without DM on global LV PSLS is similar, but the coexistence of both these factors
exerts the strongest influence at all stages of DSE.

Funding
The work was supported by a grant from the State Committee for Scientific Research
(number N N402 5002 40).

Conflict of interest: None declared.

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