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Persistent dysfunction of viable myocardium after revascularization in chronic ischaemic heart disease: implications for dobutamine stress echocardiography with longitudinal systolic strain and strain rate measurements

Assami Rösner, Derk Avenarius, Siri Malm, Amjid Iqbal, Aigul Baltabaeva, George R. Sutherland, Bart Bijnens, Truls Myrmel
DOI: http://dx.doi.org/10.1093/ehjci/jes036 745-755 First published online: 29 February 2012

Abstract

Aims Studies of functional recovery after revascularization in chronic coronary artery disease are contradictory and mark a lack of knowledge of persistent dysfunction in the non-scarred myocardium. Based on tissue Doppler-derived regional longitudinal systolic strain and strain rate (SR), both at rest and during dobutamine stress (DS), we assessed to what extent ischaemia-related reduced myocardial function would recover after revascularization in hearts with predominantly viable myocardium.

Methods and results Reference peak systolic strain and SR values were determined from tissue Doppler imaging in 15 healthy volunteers. Fifty-seven patients scheduled for coronary artery bypass grafting (CABG), with an average ejection fraction of 49%, underwent pre-operative magnetic resonance imaging (MRI) with late enhancement, resting echocardiography, and DS echocardiography (DSE), with assessment of systolic strain and SR and post-systolic strain (PSS). Eight to 10 months after CABG, myocardial function was reassessed. Forty per cent of all segments had reduced longitudinal systolic strain pre-operatively despite only 1.4% of segments with transmural infarctions on MRI. After revascularization, 38% of prior dysfunctional segments improved their resting strain, whereas 72% were improved by DS. Positive resting systolic strain indicated the absence of significant scar tissue. Resting systolic strain and DS strain responses were good prognosticators for functional improvement with areas under the receiver operating characteristic curve of 0.753 (0.646–0.860) and 0.790 (0.685–0.895), respectively.

Conclusion Persistently reduced longitudinal function was observed in more than half of pre-operatively viable but dysfunctional segments after CABG. We propose that such a functional impairment marks a regional remodelling process not amendable to re-established blood flow.

  • Strain rate imaging
  • Viability
  • Coronary artery disease
  • Dobutamine stress
  • Echocardiography

Introduction

The effects of chronic coronary artery disease (CAD) on myocardial function in humans are complex and difficult to predict. The consequences for muscle function depends on a number of factors including the severity of coronary flow reduction, time aspects of flow deprivation, medical treatment of ventricular dysfunction, and coronary dysregulation.18 Importantly, determination of myocardial viability and functional contractile reserve has been assumed to be necessary to predict recovery of function after various revascularization procedures and therefore the merit of clinical revascularization.1 Recently, however, the randomized STICH trial found no clinical benefit of revascularization of dysfunctional but viable myocardium compared with modern medical heart failure treatment alone.9 This study thus adds to the accumulating number of observations pointing to a lack of understanding of the functional and mechanistic aspects of flow deprivation and treatment effects in human chronic CAD.

Dobutamine stress echocardiography (DSE) has emerged as a versatile and simple tool to assess myocardial function and has been used extensively to determine myocardial viability and predict reversibility of ischaemia-induced reduction in functional parameters.13 Recently, regional myocardial function has been measured by the deformation parameters strain and strain rate (SR). Using tissue Doppler imaging (TDI) to assess these deformation parameters,1015 we determined segmental systolic longitudinal function of the left ventricle (LV) in patients with chronic CAD and predominately viable myocardium. Also, pre- and post-operative segmental responses to inotropic stimulation and revascularization were determined using longitudinal deformation parameters. We observed a limited normalization of longitudinal segmental function in the viable myocardium, indicating persistent dysfunction after revascularization in chronic coronary heart disease.

Methods

All patients were studied at the University Hospital of North Norway. Each underwent resting echocardiography, DSE, and late gadolinium enhancement-magnetic resonance imaging (LGE-MRI), 1–7 days before and 8–10 months after coronary artery bypass grafting (CABG), with assessment of global and regional LV functional parameters.

Patients

Between November 2005 and December 2007, 67 patients with CAD scheduled for CABG were included in the study. All patients gave written informed consent. The study was approved by the Institutional Review Board for Clinical Research. Exclusion criteria were valvular heart disease, chronic obstructive lung disease or asthma, atrial fibrillation, unstable angina, myocardial infarction within 3 months prior to CABG, left bundle branch block or any contraindications to MRI such as claustrophobia, pacemaker implants, or significantly reduced renal function as assessed by glomerular filtration rate. However, due to limited MR capacity, a maximum of two patients per week could be recruited. We aimed to include patients with both normal and moderately reduced ejection fraction (EF) and 20 patients had previous myocardial infarctions. Additionally, 15 healthy volunteers (age 44 ± 10 years, 67% male) underwent echocardiography at rest to define our normal TDI values for normokinetic myocardial segments.

Magnetic resonance imaging

All LGE-MRI images were acquired using a 1.5 T scanner (Philips Intera release 2.1, Best, The Netherlands). Fifteen minutes after infusion of 0.1 mmol/kg gadoversetamide (Optimark, Mallinckrodt, St Louis, MO, USA), LGE images were obtained, using an inversion recovery turbo-field-echo (TFE) gradient echo sequence. A five-element heart coil was used. LGE images were obtained in four-chamber, left ventricle outflow tract, and short-axis views. Imaging parameters of this 15-slice breath-hold TFE (GE) sequence were: repetition time/echo time 4.2/1.33, field of view 330 × 105 mm, 1.3 × 1.3 × 7 mm recon voxel size, TFE factor 40, number of signals averaged 1, flip angle 15°, and no parallel imaging were used. Images were analysed according to the standard 16-myocardial-segment model used for echocardiography.16 Care was taken to ensure correct alignment of the apex, mitral annulus, aortic valve, and septum. Quantification of the extent of myocardial scar tissue was performed by visual assessment of LGE images. The extent of myocardial scar tissue was grouped into three categories: ‘no scar’ (LGE = 0), ‘subendocardial scar’ (LGE = 1–49%), and ‘transmural scar’ (LGE = 50–100%). Segments were defined as viable when LGE was lower than 50%.

Echocardiography

Echo data acquisition

All echocardiographic studies were performed using an iE33 scanner (S5-1 probe, iE33, Philips Medical Systems, Andover, MA, USA) with a 1–5 MHz transducer in the left lateral decubital position. Both at baseline and during DS, conventional two-dimensional (2D) grey-scale images and TDI data were obtained in the apical two-, three-, and four-chamber views.

Acquisitions of TDI loops of five consecutive cardiac cycles were performed wall by wall in the three standard apical views, using a sector angle of 25–30° and a frame rate of 120–170 s−1. Walls were carefully aligned with the ultrasound beam. The cineloops were obtained in the DICOM format and digitally stored for off-line analysis.

Dobutamine stress protocol

β-Blockers were withdrawn 36–48 h before DSE. The test was performed using infusion rates of 2.5, 5, 10, and 20 µg/kg/min, with continuous 12-lead ECG monitoring and blood pressure measurements at the end of every 3 min stage. Conventional 2D and TDI data were acquired at baseline and at the end of each dobutamine increment. Criteria for terminating the test were completion of the protocol when 85% of the maximal heart rate (HR) was reached, severe ischaemia evidenced by extensive new wall motion abnormalities, horizontal or down-sloping ST-segment depression >2 mm, ST-segment elevation >1 mm in patients without prior myocardial infarction, severe angina, systolic blood pressure >240 or <100 mmHg, or serious ventricular arrhythmias. During DSE, the maximal Doppler velocities were increased manually from 15 to 25 cm/s in order to avoid aliasing, whereas frame rates were not changed.

Echo image analysis

The investigators of both echocardiographic and MRI data were blinded for mutual test results. All 2D and TDI measurements were analysed by a single experienced observer using commercially available software (QLAB, Philips Medical Systems). Global LV function was assessed by calculating end-systolic volume, end-diastolic volume (EDV), and EF, using the biplane Simpson' method. Stroke volume (SV) and cardiac output were derived from the calculated volumes and HR. Left atrial areas (LAA) were measured at end-systole in the four-chamber view.

Regional LV function was evaluated using the 16-segment model as defined by the American Society of Echocardiography.16 As in earlier SR imaging (SRI) studies, in the conventional 2D grey-scale loops, myocardial segments were scored as normal (score = 1), moderately hypokinetic (2), severely hypokinetic (2.5), akinetic (3), or dyskinetic (4).11 Data from segments with poor image quality were discarded. All septal segments, non-revascularized segments (according to the surgical report), and segments with increased post-procedural LGE were excluded from statistical analyses.

For TDI strain analysis, each segment was tracked manually by positioning a region of interest (ROI) with a length between 1.0 and 1.8 cm, and a width of 0.25 cm in the centre of the myocardial wall throughout five cardiac cycles. The system calculates cosines' α corrected SR. Axial averaging of SR at a length of 1 cm and weighted temporal smoothing were applied. Measurements were discarded in segments with aliasing, missing Doppler data for more than 50% of the cardiac cycle, large reverberations, and angle deviation over 25°, when velocity and SR curves lacked E-waves and when curve shape and peak values changed more than 20% from beat to beat. Additionally, the uniformity of strain curves derived from five to eight divisions along the ROI served to assess visually data quality.

The aortic valve opening and closure, and thereby the ejection time (ET) period, were determined by Doppler detection of the aortic valve clicks. SR was expressed as the mean of all SR values during ET, and ET strain was defined as the highest positive or negative peak strain value during ET. Post-systolic strain (PSS) was then defined as the difference between peak ET strain and peak strain. The ratio PSS/ET strain was expressed as the post-systolic strain index (PSI). In a cineloop of five cardiac cycles, the first cycle was analysed, except in the case of extrasystoles or insufficient quality of the first beat. Then, the second or following cycles were analysed.

For wall motion scores (WMS), ET strain, SR, and PSI, the highest values from all dobutamine doses and the peak increment between the resting value and maximal values were extracted. In the healthy volunteers, 97.5% of ET strain values were less than or equal to −10.3%. This 97.5% percentile for segments in normal individuals was chosen as a cut-off to define dysfunctional myocardium. The histograms of both groups are shown in Figure 1. Definitions of different ischaemic substrates and cut-off values are listed in Table 1. The cut-off for akinesia was arbitrarily set at ET strain greater than −4.0%. Consequently, hypokinesia was defined as ET strain between −10.3 and −4.0%. Four groups of DSE strain increments were defined as described in Table 1, whereas the cut-off of −7.5% between moderate DS increment (DSE+) and low DS increment (DSE−) was extracted from the receiver operating characteristic (ROC) curve for functional improvement of all dysfunctional segments. Cut-offs for ‘no DS strain increment’ (DSE− −) (−1%) and ‘high DS strain increment’ (DSE++) (−15%) were selected arbitrarily.

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Table 1

Overview over definitions of segmental ischaemic substrates

Viable segmentLE-MRI <50%
Transmural scarLE-MRI 50–100%
Subendocardial scarLE-MRI 1–49%
HypokinesiaResting ET strain: −10.3 to −4%
AkinesiaResting ET strain: greater than −4%
Dysfunctional segmentResting ET strain: greater than −10.3%
DSE− − (no DS response)DSE strain increment: −1.0–0.0%
DSE− (low DS response)DSE strain increment: −7.5 to −1.01%
DSE+ (moderate DS response)DSE strain increment: −15.0 to −7.51%
DSE++ (high DS response)DSE strain increment: less than −15.0%
ET strain improvement after CABG(ET strain post-CABG) – (ET strain pre-CABG) ≤ −4.4 and ET strain post-CABG ≤ −4.4
No ET strain improvement after CABG(ET strain post-CABG) – (ET strain pre-CABG) > −4.4 or ET strain post-CABG > −4
DSE improvement after CABG(DSE strain increment post-CABG) − (DSE strain increment pre-CABG) ≤ −4
  • The first 10 definitions are based on pre-operative data only, while the last 3 rows express the difference between pre- and post-operative ET strain.

Figure 1

Histograms of resting ejection time strain in the normal population and coronary artery disease patients. A cut-off a 97.5 percentile at ejection time strain of −10.3% reveals 39% of dyskinetic segments in coronary artery disease patients.

Regional functional improvement was defined as the pre- and post-operative difference in ET strain of at least 4.4% [=1 standard deviation (SD) of the Bland–Altman plot for intraobserver variability]. Segments not improving beyond strain values of −4% were also considered ‘unimproved’.

Reproducibility

To determine interobserver variability for TDI strain and SR, 15 patients with moderately reduced EF (44 ± 9%) were randomly selected, and another independent, experienced observer (S.M.), who was blinded to all other data, analysed the pre-operative data at rest and peak dobutamine dose. For assessing intraobserver variability, data from the same 15 patients were reanalysed by the main observer (A.R.) in a new random order after at least 6 months.

Statistical analyses

If not stated otherwise, all data are expressed as mean ± SD. Paired Student's t-tests were used to test changes before and after CABG. Differences between functional parameters of normokinetic, hypokinetic, and akinetic segments or parameters of healthy individuals and CAD patients with normal and reduced EF were tested by one-way ANOVA with the Bonferroni post hoc analysis. The difference between improved and unimproved groups was analysed by a Student's t-test. General estimated equations with binary logistic regression were used to test segmental differences between these groups for global parameters, correcting for the same data distributed in different groups. Univariate linear regression analyses were performed to test the ability of segmental parameters in predicting strain improvement. χ2 tests were used to compare the number of improved and not improved segments of different ischaemic subgroups. Cut-off values from one-half of the data set were extracted using ROC curves. Sensitivity and specificity were calculated from the other half of the data. Sequential Cox's proportional hazard models were used to correct ROC curves for clustered data. Results are expressed as area under the curve (AUC), P-value, and 95% confidence interval (CI) for AUC. Probability values <0.05 were considered statistically significant.

Inter- and intraobserver variabilities for strain and SR were expressed as the absolute difference between two measurements in per cent of their mean.17 To avoid the problem of increasing variation with a denominator close to 0, a constant of −25 was added to all measured strain and −2.5 to all measured SR− values. In assessing variability, percentages of less than 20% were regarded as fair and less than 15% as good results. All statistics were performed by SPSS version 16.0 (SPSS Inc., Chicago, IL, USA).

Results

Patient and myocardial segment exclusions

Of the 67 enrolled patients, five were excluded from the study prior to CABG due to atrial fibrillation (n= 1), claustrophobia (n= 2), or logistic problems (n= 2). Additionally, five patients did not complete the post-operative protocol; one due to loss of data, one refused a second MRI, and three had declining health after the surgical procedure. Thus, 57 patients were included in the final analysis. Table 2 displays the patient characteristics.

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Table 2

Patient characteristics

Values% or ±SD (range)
Total in both studies (n)57100
Men (n)5596.5
Age (years)62.4±8.89 (39–83)
Height (m)1.75±0.06 (1.58–1.90)
Weight (kg)87±12 (51–117)
Cholesterol treated (mmol/L)4.84±0.96 (3.00–6.75)
Diabetes II (n)1221.1
Hypertension (n)2442.1
History of Smoking (n)2543.8
Family History of CAD (n/%)3357.9
β-Blockers (n)57100.0
Angina before CABG (n/%)5189.5
Positive treadmill test (n/%)3866.0
Angina or a positive treadmill test (n/%)5596.5
Previous MI (n/%)2034.6
Previous PCI1729.8
1-vessel disease (n/%)1424.6
2-vessel disease (n/%)1933.3
3-vessel disease (n/%)2136.8
Main stem stenosis (MS) alone (n/%)30.05
MS and 1 vessel (n/%)23.5
MS and 2 vessel (n/%)814.0
MS and 3 vessel (n/%)814.0
Normal EF (>55%) (n/%)2238.5
EF (41–54%) (n/%)2950.9
EF (22–40%) (n/%)610.5
EF (%)49.2±8.8 (22–65)
Patients with LGE 1–100% (n/%)1526.3
Patients with LGE 50–100% (n/%)712.3
Patients with LGE 1–49% (n/%)1221.1
Hypokinetic segments by ET strain (n/%)103/41524.8
Akinetic segments by ET strain (n/%)59/41514.2
Normokinetic segments by ET Strain (n/%)253/41561.0
Hypokinetic segments by WMS (n/%)147/42837.4
Akinetic segments by WMS (n/%)32/4288.1
Normokinetic segments by WMS (n/%)214/42854.3
EDV before CABG (mL) (SD/CI)134±35 (125–144)
EDV after CABG (mL) (SD/CI)128±31 (120–137)
EF before CABG (%) (SD/CI)53±9 (50–55)
EF after CABG (%) (SD/CI)51±8.7 (48–53)
  • WMS indicated the same amount of dysfunctional segments as strain measurements. EDV and EF were not significantly different before and after CABG.

We excluded the following segments from data analyses: all septal segments, due to their known deterioration after cardiothoracic surgery18 (285/912 segments), segments with increased LGE post-CABG indicating peri- or post-operative infarctions, defined as increments exceeding 25% LGE (28/627 segments), and diseased segments not revascularized according to the surgical report (60/627 segments). Due to low quality, in LGE-MRI, 4 segments were discarded before and 24 segments after CABG, while 87/912 (9.54%) segments were discarded after DSE and before CABG and, finally, 128/912 (14.0%) post-operatively. All together, 428 segments were left for statistical analyses.

Longitudinal ejection time strain in patients with high-grade coronary artery disease

Compared with the 97.5% percentile obtained from the healthy reference group, longitudinal resting ET strain was reduced in 39.0% of all segments in the CAD patients (Figure 1). Only 6.7% of all segments were LGE-positive wherefrom 1.4% of all segments had transmural scars. Table 2 displays the number of hypokinetic and akinetic segments defined by WMS or SRI. The numbers of dysfunctional hypokinetic or akinetic segments by either method were comparable. In the present patient group, the overall pre- and post-operative volumes and EF were unchanged.

Table 3 displays global and longitudinal segmental function parameters in healthy volunteers and CAD patients with normal EF and reduced EF. A comparison of the healthy population and patients with severe CAD but normal EF revealed substantially decreased longitudinal strain, SR, WMS, and increased PSS in the CAD patients, even though global functional parameters were equal. Patients with reduced EF had a further decline in regional functional parameters.

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Table 3

Resting echocardiographic parameters

Healthy populationCAD patients EF > 55%CAD patients EF < 55%
MeanSDMeanSDMeanSD
n = 15n = 21n = 36
EF (%)61±360±546*,†±8
EDV (mL)112±25120±30149*,†±39
ESV (mL)44±1048±1482*,†±30
SV (mL)69±1572±1767±16
CO (mL/min)4339±9744916±11044758±1392
LAA (cm2)15.4±3.317.7±3.819.4*±3.5
n = 232n = 311n = 514
WMS1.0±0.01.3*±0.51.4*,†±0.7
ET strain (%)−18.9±5.9−15.2*±10.2−13.1*,†±10.1
ET-SR (−1)−0.52±0.27−0.43*±0.34−0.41*±0.41
PSS (%)0.1±0.1−1.2*±2.6−2.0*,†±3.2
  • Comparison between CAD patients with normal and reduced EF and healthy individuals. Reduced segmental longitudinal function and increased PSS indicate a substantial decrease in myocardial function in CAD patients independent of EF and other global functional parameters. Segmental functional parameters decrease further in parallel with EF reduction.

  • *Significant difference between healthy individuals and CABG patients of each EF group, P< 0.005.

  • Difference between CAD patients with EF > 55% and EF < 55% with P< 0.05.

Improvement of resting function and contractile reserve

Figure 2 displays strain curves at rest and during low-dose DSE, demonstrating an apical segment with positive strain and high DS response. This type of response marked a high probability of functional recovery. Figure 3 shows dysfunctional segments divided by pre-operative LGE-MRI and DS response. Among viable segments (LGE-negative + LGE 1–49%) with dysfunction, only 38% improved their resting function after CABG. All LGE + segments had no ability to improve resting longitudinal function. High DS response was highly indicative for improvement of resting function, whereas a low- or no DS response indicated no functional improvement. However, either resting ET strain or DS response after CABG was improved in 72% of all segments. Only transmural scars indicated no detectable post-operative contractile reserve.

Figure 2

Strain curves with positive longitudinal ejection time strain in the apex and strain increment during dobutamine stress echocardiography, indicating preserved tissue elasticity and the ability to improve function after revascularization.

Figure 3

Improving and non-improving dysfunctional segments. Thirty-eight per cent of segments improved resting function, while 72% improved either resting ejection time strain or dobutamine stress response. Segments with pre-operatively low dobutamine stress response (DSE− − and DSE−), hardly improved resting ejection time strain after coronary artery bypass grafting. Contrarily, segments with pre-operatively high dobutamine stress response (DS++) were most likely to improve resting function after coronary artery bypass grafting. The groups of segments with any degree of late gadolinium enhancement and segments with moderate dobutamine stress response (DSE+) had low chance for improvement of resting ejection time strain, while only transmural late gadolinium enhancement indicated no improvement of dobutamine stress response or resting ejection time strain. Notations in the graph above indicate significant differences in the ratio improving to non-improving segments compared with *DSE+ and DSE++.

Prediction of functional improvement

Table 4 displays the values of global and segmental parameters in patients with varying degrees of myocardial dysfunction and contains an analysis of factors predicting functional improvement after revascularization. ‘DSE highest strain’ and ‘DSE strain increment’ were the only segmental parameters predicting improvement after CABG in pre-operatively hypokinetic segments. In pre-operatively akinetic segments, however, PSS, DSE peak values of strain and SR, DSE strain and SR increments, lower LAA, and higher EF all indicated higher probabilities for functional improvement. Interestingly, positive peak ET strain indicated high probabilities for functional improvement.

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Table 4

Preoperative resting and dobutamine stress echocardiographic parameters in left ventricular segments

 NormokinesiaHypokinesiaAkinesia
ImprovedNot improvedImprovedNot improved
n= 253n= 39n= 64n= 29n= 30
Stroke volume (mL)71 ± 1667 ± 1766 ± 1768 ± 1667 ± 17
Cardiac output (mL/min)4934 ± 12744551 ± 11474700 ± 12434761 ± 10054601 ± 1200
EF Simpson (%)54 ± 854 ± 951 ± 11*,†52 ± 1047 ± 11
End-diastolic volume (mL)134 ± 34127 ± 42134 ± 42136 ± 36146 ± 39
End-systolic volume (mL)62 ± 2461 ± 3169 ± 3368 ± 2979 ± 33
Left atrial area (mL)18.5 ± 3.817.9 ± 3.519.2 ± 3.5*17.7 ± 4.120.1 ± 3.0*
Wall motion score (WMS)1.3 ± 0.51.4 ± 0.41.6 ± 0.71.8 ± 0.81.8 ± 0.9
ET strain (%)−20.1 ± 6.1−8.4 ± 2.4−8.4 ± 2.33.9 ± 5.4−1.1 ± 2.8*,†
ET-SR (−1)−0.61 ± 0.41−0.24 ± 0.13−0.21 ± 0.140.04 ± 0.23−0.05 ± 0.10*,†
Post-systolic index0.1 ± 0.10.2 ± 0.40.2 ± 0.33.0 ± 34.43.7 ± 13.0
Post-systolic strain (%)−1.2 ± 2.2−1.8 ± 2.9−1.6 ± 2.6−4.4 ± 4.9−2.4 ± 2.4*,†
DSE: highest WMS1.1 ± 0.31.2 ± 0.41.3 ± 0.6†2.5 ± 0.8†2.4 ± 0.7†
DSE: highest strain (%)−26.7 ± 8.2−17.7 ± 7.1−15.0 ± 5.9*,†−11.8 ± 10.9−6.2 ± 4.7*,†
DSE: highest SR (−1)−1.19 ± 0.57−0.75 ± 0.44−0.66 ± 0.36−0.54 ± 0.49−0.29 ± 0.21*,†
DSE: WMS increment0.2 ± 0.40.3 ± 0.40.3 ± 0.40.3 ± 0.50.3 ± 0.4
DSE: strain increment (%)−6.6 ± 6.6−9.3 ± 6.6−6.7 ± 5.7*−15.8 ± 13.2−5.0 ± 4.0*
DSE: SR increment (−1)−0.58 ± 0.48−0.51 ± 0.41−0.45 ± 0.36−0.59 ± 0.57−0.24 ± 0.21*
DSE: PSI increment−0.5 ± 1.5−0.8 ± 2.1−1.1 ± 1.76.0 ± 13.012.0 ± 43.3
  • Mean values and SD of improved and not improved segments in hypokinesia vs. akinesia for echocardiographic global and segmental functional parameters. Highest DSE values indicate the peak value of the whole DSE test; DSE increments: difference between highest values and the resting value. Notations: significant differences in groups with improved and not improved segmental resting strain after CABG (bold and *); significant differences comparing akinetic or hypokinetic segments with normokinetic segments (†).

Table 5 presents the results of a univariate linear regression analysis of segmental function parameters. Preoperative ET strain and DSE strain increments correlated best with the improvement of post-operative ET strain. Only these two parameters were independent predictors of functional improvement in a multiple regression analysis. However, creating a combined parameter: ‘Sum: ET strain and DSE strain increment’ = (0.59 × ET strain) − (0.65 × DSE strain increment), did not significantly improve the correlation coefficient. Figure 4 shows ROC curves for ET strain improvement after CABG. The prognostic values of the three tested parameters (ET strain, DSE strain increment, and ‘Sum: ET strain and DSE strain increment’) were fair in akinetic segments and poor in hypokinesia.

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Table 5

Univariate regression analysis for ejection time strain improvement after coronary artery bypass grafting

 RR2P-valueCI
Lower boundUpper bound
ET strain (%)0.5700.325<0.001−0.7−0.6
ET-SR (−1)0.4550.207<0.001−14.46−9.90
Post-systolic strain (%)0.1440.0210.0030.20.9
Wall motion score (WMS)0.1430.0210.0040.94.5
DSE: highest WMS0.1100.0120.0260.34.7
DSE: highest strain (%)0.2240.050<0.001−0.3−0.1
DSE: highest SR (−1)0.1510.0230.002−4.67−1.08
DSE: WMS increment0.0840.005n.s.−5.10.4
DSE: strain increment (%)0.4150.172<0.0010.50.7
DSE: SR increment (−1)0.2210.049<0.0013.137.69
DSE: PSI increment0.0640.004n.s.−0.00.2
Sum: ET strain + DSE strain0.6130.375<0.0010.981.25
  • Resting and DSE parameters and the correlation between the amount of DSE strain improvement after CABG. ET strain and DSE strain increment had the highest correlation coefficients showing significant results in regression analysis. The sum of ET strain and DSE strain increment showed improved correlation coefficients.

Figure 4

Receiver operating characteristic curves, sensitivities, and specificities for the identification of functional improvement after coronary artery bypass grafting in all segments and segments with hypokinesia or akinesia. Unexpectedly, dobutamine stress and resting strain were good predictors of functional improvement in hearts with low amount of scar tissue. This effect is probably due to inclusion of positive strain in akinetic/dyskinetic segments.

Positive strain as an indicator for viability

Figure 5 demonstrates that positive strain is a significant predictor for functional improvement. Segments with LGE and segments with no or low DS response were not represented in this functional group, indicating preserved tissue elasticity in segments with positive strain, viability, and a high ability to improve resting function. All segments with positive strain improved either resting function or DS response.

Figure 5

Percentage of all segments with lesion characteristics in different ejection time strain groups. Yellow to red: indicating improvement of function; violet to blue: indicating no functional improvement. The probability of functional improvement was highest in segments with positive ‘dyskinetic’ ejection time strain. Segments with late gadolinium enhancement and segments with low or no dobutamine stress response were not ‘dyskinetic’, indicating preserved tissue elasticity in this group with positive ejection time strain.

Reproducibility

For intra- and interobserver variability, 386 segments were analysed; half were segments at rest and half analysed during DS at the highest dobutamine dose used. The coefficient of variation for intraobserver variability for ET strain and mean SR was 9.6 and 6.5%, respectively. The repetition coefficient (2 × SD) for ET strain values in the Bland–Altman plot was ±8.8% (see Supplementary data online, Figure S1). The coefficient of variation for the interobserver variability was 10.3% for ET strain and 7.6% for mean SR.

Discussion

This study demonstrates that longitudinal function was reduced in a high amount of segments in hearts with diffuse CAD. In this representative surgical CAD patient population, only 38% of segments subsequently improved their resting longitudinal function after grafting. However, contractile reserve improved in the majority (72%) of viable segments as demonstrated by a positive response to inotropic drugs. Functional improvement was predicted by DS in non-scarred segments. Additionally, resting segmental positive strain proved to be a good indicator of the pre-operative absence of scar tissue and a predictor of functional improvement after successful grafting. It is important to notice that the majority of patients in this study had normal or near-normal LV function.

Longitudinal ejection time strain in patients with high-grade coronary artery disease

To our knowledge, this is the first study using longitudinal segmental strain to define resting myocardial dysfunction and functional improvement in CAD patients pre- and post-CABG. Longitudinal systolic strain proved to be a less subjective parameter than the traditionally used WMS. It correlated well with relatively minor ischaemic changes in the inner myocardial layers, where predominantly longitudinal fibres are most prone to ischaemia and repetitive stunning.10,19

Even though the normal population in our study was small and younger than the patient group, values defined as normal are in accordance with cut-off values for strain derived from the HUNT study on 1266 healthy individuals.20 In the HUNT study, investigating males older than 60 years, normal ET strain was ≥10.7%, whereas the cut-off strain in the present study was ≥10.3%.

Using these cut-off values in the present study, myocardial segmental function in CAD patients was equally reduced when expressed by WMS or longitudinal ET strain. It has been shown that global strain and EF correlate well under different contractile states.12,21 The results of the present study thus indicate that regional longitudinal function and WMS are both reduced in high-grade CAD when EF is still normal. Thus, longitudinal strain and SR, PSS, and segmental WMS are sensitive markers for early myocardial dysfunction in CAD while EF is not.

Improvement of resting function and contractile reserve

Traditionally, improvement of resting function after revascularization has been thought to reflect the absence of transmural scars and thus indicating viability. Earlier studies on the effect of CABG in heart failure patients with high percentages of scar tissue have reported an improvement in 78–83% of viable segments already 6–9 months after surgery.14,22,23 In contrast, in the present study, the percentage of recovering dysfunctional segments was much lower (38%). This discrepancy could possibly be explained by the associated major changes in loading in dilated failing hearts.24 LVs with low EF have increased wall stress that often is reduced post-operatively through re-remodelling and the effect of drug therapy.3 In the present study, however, most of the patients had normal or nearly normal EF with low potential for improvement of global function measured by SV or EF. Postoperative re-remodelling was therefore not prominent. In accordance with this hypothesis, an unchanged post-operative EDV and blood pressure indicate unchanged ventricular geometry and wall stress. Thus, in our patients, strain improvements had a higher probability of expressing ‘true functional improvement’ meaning recovery of contractile force in contrast to ‘pseudo-functional improvement’ due to reduced wall stress at unchanged contractile force at rest.

The present study showed that any improvement in DS response (72% of dysfunctional segments) in addition to improvement at rest (38% of dysfunctional segments) better reflected a recovery potential than resting function alone in segments without transmural infarction. This finding also indicates that the absence of transmural scar tissues does not necessarily implicate improving function at rest. For example, viable segments with no or low DS response have probably no flow reserve and suffer high-grade ischaemia before revascularization.25 These viable segments with low DS response had no ability to improve resting function. However, nearly all segments with low DS response before CABG regained contractile reserve after revascularization.

Prediction of functional improvement

In the present study, DS response and resting strain were the best predictors for functional improvement in longitudinal strain. In accordance with previous studies,10,11,13,14,26,27 no DS response was a highly accurate predictor for no functional improvement and a high DS response indicated a high probability of functional improvement. However, intermediate results led to low test accuracies in hypokinetic segments. The relatively low number of segments with subendocardial and transmural scars and consecutively high EF in our patient population might have a high impact on predictivity in terms of lower test accuracies. Additionally, the medication with β-blockers might also influence the prediction of functional improvement. Even though all patients were medicated with β-blockers, the DS test was performed 36–48 h after withdrawal. However, high β-blocker dosage might have caused blunted test results. Anyhow, a previous study on patients without β-blocker withdrawal has shown that performing low dose DS at maximal doses of 20 µg/kg/min significantly improved test accuracies.28 Interestingly, we could demonstrate that both the presence of subendocardial scars and no DS response (in viable tissue indicating no flow reserve) were good predictors for functional non-recovery in viable segments as defined by the MR technique.

Positive strain as an indicator for viability

Expressing ET strain by the highest negative or positive value during ET is a novel approach applied under the assumption that positive strain might express preserved tissue elasticity. Traditionally, strain has been expressed as the maximal negative value during ET.10,11,13,14,26,27 By distinguishing predominantly positive ‘dyskinetic’ or akinetic strain, we found positive strain to be a marker for the absence of LGE. Segments with LGE have probably reduced tissue elasticity and thus behave hypokinetic or akinetic instead of ‘dyskinetic’ giving positive strain. Of note, when positive longitudinal strain was present, segments had not only high probability of functional improvement; the majority of segments even normalized their function.

Limitations of the study

Segmental tissue-flow measurements with sufficiently high spatial resolution are difficult to apply in the clinical setting and were not attempted in our study. The measurement of tissue flow would have been advantageous to differentiate reduced segmental flow reserve and segmental dysfunction with normal flow. Furthermore, segmental biopsies could have been able to demonstrate structural myocardial damage in the absence of myocardial scars detectable by MRI. Contrarily to other viability strain studies,10,11,13,14,26,27 we have studied CABG patients only. CABG itself might have deteriorating influence on post-interventional strain, especially in the septum.18 However, we excluded the septal segments, in which long-term decreased longitudinal function is a known phenomenon.

In spite of these methodological limitations, the reduced recovery of deformation indexes was demonstrated in the limited number of 57 patients with small amounts of scar tissue. Thus, the study indicates that more in-depth studies can be done with selected methodology in relatively small number of patients. A 2-year follow-up might have revealed a higher percentage of recovering segments as demonstrated by Bondarenko et al. (95%).22 However, such a prolonged observation period could have seen a disease progression with functional deterioration. Resting ET strain has probably only prognostic relevance when differentiating positive strain from negative to zero strain. The cut-offs for group definitions were more or less set arbitrarily. Therefore, the favoured test parameters were chosen according to the regression analysis.

Implications and conclusion

Results from the ‘STICH’ trial9 indicate that the traditional viability testing before medical or surgical treatment has no significant impact on the patient prognosis. Additionally, our study indicates that resting regional functional parameters are particularly unresponsive to revascularization in hearts with near-normal global LV function. The pathophysiological substrate for these observations remains to be clarified, but the observations point to a complex relation between the degree and time course of chronically reduced blood flow and recovery of myocardial function, also in hearts with well-preserved global function.

References

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