Exploratory echocardiographic strain parameters for the estimation of myocardial infarct size in ST‐elevation myocardial infarction

Abstract Background Outcome after ST‐elevation myocardial infarction (STEMI) can be most reliably estimated by cardiac magnetic resonance (CMR) imaging. However, CMR is expensive, laborious, and has only limited availability. In comparison, transthoracic echocardiography (TTE) is widely available and cost‐efficient. Hypothesis TTE strain parameters can be used as surrogate markers for CMR‐measured parameters after STEMI. Methods TTE strain analysis was performed of patients included in a controlled, prospective STEMI trial (NCT01777750) 4 ± 2 days after the event. Longitudinal peak strain (LPS), post‐systolic shortening, early systolic lengthening, early systolic lengthening time, and time to peak shortening were measured, and index parameters were computed. Global longitudinal strain (GLS) and ejection fraction (EF) were compiled. Parameters were correlated with CMR‐measured variables 4 ± 2 days after STEMI. Results In 70 STEMI patients, high quality CMR and TTE data were available. Highest correlation with CMR‐measured infarct size was observed with GLS (r = 0.577, p < 0.0001), LPS (r = 0.571, p < 0.0001), and EF (r = −0.533, p < 0.0001). Highest correlation with CMR‐measured area at risk was observed with GLS (r = 0.666, p < 0.0001), LPS (0.661, p < 0.0001) and early systolic lengthening index (r = 0.540, p < 0.0001). Receiver operating characteristics for the detection of large infarcts (quartile with highest infarct size) showed the highest area under the curve for LPS, GLS, EF, and myocardial dysfunction index. Multiple linear regression displayed the best association between GLS and infarct size. Conclusion Exploratory strain parameters significantly correlate with CMR‐measured area at risk and infarct size and are of potential interest as endpoint variables in clinical trials.

past, superiority in interstudy reproducibility of CMR compared to 2D TTE was shown. 10 Infarct size cannot be measured by TTE, but functional parameters reflecting necrotic segments and stunned myocardium can be measured. Strain analysis applying speckle tracking in TTE images quantifies deformation of myocardial segments. It is an algorithm-based technique, which reduces investigator bias and is already used in clinical routine to estimate cardiac function. Global longitudinal strain (GLS) has become an established parameter. Changes in GLS are related to ischemic regions as validated by contrast-enhanced CMR. 11 Other strain parameters, such as post-systolic shortening (PSS) and post-systolic shortening index (PSI), were predictive of heart failure in patients after STEMI. 12 Post-systolic shortening and wall thickening are known as parameters reflecting ischemia and short-term hibernation. 13,14 Further parameters of interest are early systolic lengthening (ESL), early systolic lengthening index (ELI), and myocardial dysfunction index (MDI). 15,16 Improved ultrasound technology allows to evaluate TTE variables as potential surrogate endpoints in clinical trials. Furthermore, novel strain measurements might be useful in routine patient care as prognostic and surveillance parameters.
In the present study, we aimed to assess 2D strain parameters as surrogate markers compared to CMR-measured parameters in STEMI patients who were included in a controlled, prospective study.

| Patients
Patients included in the present study were participants of the controlled, randomized, prospective strategic targeted temperature in myocardial infarction (STATIM) trial, in which mild therapeutic hypothermia (MTH) was compared with standard care regarding AAR after STEMI. The primary endpoint was MSI as measured by CMR. 5 All primary and secondary endpoints were negative. 17

| Cardiac magnetic resonance
Cardiac magnetic resonance (CMR) was described in detail before. 17 The volume of the entire left ventricular myocardium was assessed. Infarct size was measured 4 ± 2 days after pPCI using a 1.5 T system (Avanto Fit, Siemens Healthineers) delineating late gadolinium-enhanced (LGE) myocardium in short-axis views ( Figure 1, Panel A, B). The percentage of infarcted area relative to total myocardium was calculated. In addition, the edemabased AAR, by T1 and T2 mapping, and MVO, delineated as hypoenhanced infarct core area in LGE studies were measured. CMR was conducted using standardized protocols. 18 For late gadolinium enhancement, 0.15 ml/kg gadobutrol (0.1 mmoL/ml, Gadovist, Bayer) was administered.
Left ventricular volumes and ejection fraction (EF) were assessed. Patients were divided into quartiles according to infarct size. A cardiovascular radiologist processed and evaluated the images using the QMass postprocessing software package (Medis Medical Imaging).

| Echocardiography
Echocardiographic studies were performed by experienced observers on a GE Vivid E9 4 ± 2 days after pPCI. Speckle tracking analysis was performed using specific software ( Figure 1  to the maximum overall shortening (Figure 2 3 | RESULTS

| Patients
Patients, from whom high quality CMR and TTE data were available, were included in the analysis (n = 70). Mean age was 56 ± 10 years, the majority of patients were male (19% female). Detailed baseline characteristics are displayed in Table 1.

| TTE-measured strain parameters correlate with CMR-measured infarct size and AAR
Significant correlations with infarct size were observed for GLS  Table S5. Significant AUCs are displayed in Figure 4.
A multiple linear regression model applying a stepwise approach revealed a significant association between EF, GLS, and infarct size (F

| DISCUSSION
In the present study, we evaluated a broad set of echocardiographic strain parameters as outcome variables after STEMI compared to CMR-measured parameters. This data set may build a basis for further evaluation of strain parameters as surrogate marker endpoints in STEMI intervention trials.
The study cohort of the present study were participants of a prospective STEMI trial, in which MTH was tested as an adjunctive therapy. In line with CMR endpoint results, we observed no differences in echocardiographic measurements between the treatment groups (data not shown).
Strain analysis in TTE has evolved rapidly in the past 10 years, 20 and GLS is broadly used to assess left ventricular function in daily routine. Recently, it was shown that GLS has superior prognostic value over EF measurements in heart failure. 22 Moreover, strain analysis algorithms provide a large data set beyond GLS. The amount of shortening for every segment at every time point during the cardiac cycle is displayed. Dyssynchronous contraction patterns, shortening during diastole, or lengthening during systole can be observed. Lengthening at the beginning of systole, the ESL, is displayed in percent of the overall length of the myocardium for each acoustic window. 23 The corresponding index (ELI) can be interpreted as the amount of lengthening in relation to the overall shortening in percent. Shortening of the myocardium after aortic valve closure (PSS) has already been recognized as a sensitive parameter in coronary artery disease several years ago. 24 The corresponding index (PSI) can be interpreted as the amount of shortening occurring after aortic valve closure in relation to the overall shortening in percent. The MDI, which combines ESL and PSS and describing the proportion of 'wasted work', was recently introduced. 16 This wasted work impacts negatively on cardiac output and must be compensated by the remaining myocardium. The mechanical interaction between infarct, border, and remote normal zone leads to an impaired myocardial performance with dyssynchronous contraction of the different segments. 25 Furthermore, ELT and TTP were investigated in patients with ischemic heart disease. 15