The ASTAMI study, which included 100 patients, was originally designed with a power of 80% to reveal a potential difference of 5% points of LV EF development between the mBMC and the control groups as measured by single-photon-emission computed tomography. No difference was found for global functional development or for clinical parameters[2
]. For LV EF inter-observer variability was assessed with ICC of 0.85 (0.67-0.93) for FLASH cines and ICC of 0.98 (0.96-0.99) for trueFisp cines[2
] (Supplementary Appendix). In this substudy, only 28 patients were included, resulting in reduced power. Unlike previous reports, myocardial wall function developed beneficially for the control group as compared with the mBMC group. Strain improvement was 2.5 ± 2.0% points in the infarct zone and 1.6 ± 1.8% points globally. Infarct mass as shown by LGE developed similarly to strain, with a more pronounced infarct mass reduction for the controls than for the mBMC group. Both groups had a parallel, but statistically non-significant trend towards LV EF improvement. The results from this study illuminate the potentials for detailed regional myocardial examination to detect subtle differences of myocardial function not always detected by other examination techniques routinely used.
Care must be taken drawing conclusions from the results regarding development of myocardial function and LGE in this study. Recently, Beitnes et al. published results from the long-term follow-up of the ASTAMI trial including global and regional LAD strain analyses performed with longitudinal two-dimensional speckle-tracking echocardiography (2D STE)[10
]. They reported a significant improvement of regional and global peak systolic strain from baseline to 6 months, which was maintained at three years post-infarction. However, there were no significant differences between the groups regarding change in myocardial systolic or diastolic function. The present substudy introduces some methodological refinement to this study. Circumferential strain was calculated from short axis CMR tagging versus longitudinal strain calculation from long axis 2D STE. For the regional CMR tagging analysis the infarct zone was directly defined by findings from baseline LGE, achieved during the same image session. Inter- and intra-observer strain reproducibility was excellent for global and regional strain analyses, even though reproducibility decreased when strain was studied on the individual segmental level. For the echo examination there was no opportunity to directly delineate the myocardial infarct area, and the region studied was the predefined LAD territory. Additionally, strain calculations were made at different time points. Baseline of the echo study was 4.5 ± 1.1 days after the myocardial infarction, before the bone marrow aspiration and intracoronary mBMC injection of the mBMC group, whereas the baseline CMR examination was performed at 18.8 ± 3.8 days. This fact is also relevant for the comparison of the global LV volumetric analyses. Even though the groups did not develop significantly differently, the CMR examinations in the main ASTAMI study revealed a larger increase of LV EF (1.2% vs 4.3%, p = 0.054), and a larger decrease of infarct size (-2.3 vs -5.9 ml, p = 0.11) in the control group than the mBMC group[2
]. There were no between-group differences in baseline infarct mass in the larger, main ASTAMI study. Although not significant, the baseline infarct mass in the substudy was slightly, but not significantly higher in the control group than in the mBMC group. Strain values in the ischemic heart are closely related to LGE[22
], and strain improves over time after acute myocardial infarction[25
]. In the present study, there was a significant correlation between improvement of strain and reduction of infarct size in the control group (Table ). Part of the differences between the study groups may have been caused by the small study group bias.
In the main ASTAMI study, 72% of the patients who received intracoronary cell injections reported mild chest pain during the procedure and 77% had transient ischemic ST deviation during balloon inflation. No patient had reinfarction related to the procedure[2
]. Beitnes et al. recently reported no adverse effects observed after three years in the same population[21
]. Thus, there is no indication that the intracoronary balloon inflation procedure has influenced the clinical results of the mBMC group. The present study was not designed to reveal any subtle immediate beneficial or unfavorable changes in the myocardium after intracoronary injection of mBMC. One might speculate, however, that recurrent balloon inflations might negatively influence myocardial function in the treatment perfusion area, as indicated in our results.
Regional wall function has been investigated by different means in other stem cell trials. In the Repair-AMI trial regional function improved more in infarcted areas in the stem cell group judged by the centerline chord method at 4 months[6
]. In a recent CMR substudy by Dill et al., infarct area wall thickening was assessed by cine CMR examination, and the results indicated more pronounced increase of wall thickening in the stem cell group after 12 months in the group of patients with initial EF lower than median EF (48.9%)[9
]. In the BOOST trial, wall thickening and wall motion in infarcted areas were studied by short axis cine CMR. There was no significant treatment effect from stem cell injection on global LVEF or on the regional function parameters studied at 18 months or 5 years follow up[7
]. In the trial from Leuven wall thickening was assessed by short axis cine CMR in transmurally and non-transmurally infarcted segments. The change in systolic function did not differ at 4 months between the stem cell group and the placebo group[5
]. However, there was a beneficial stem cell treatment effect on strain as measured by tissue Doppler imaging for segments with initial LGE involvement of more than 75%[8
]. The results from our substudy do not support any potential beneficial effect from intracoronary injection of mBMC after reperfused myocardial infarction. This also applies to the patients with larger transmural myocardial infarcts and those with low EF.
End systolic LV twist is the difference in the systolic clockwise rotational movement of the basal region from the counter-clockwise rotational movement of the apical region as seen from the apex. The rotation is part of the complex wringing movement of the left ventricle during systole[27
]. Baseline end systolic LV twist values in our study were 11.3 ± 3.6°and 12.8 ± 5.4°in the mBMC group and controls, respectively. Despite lack of healthy controls for comparison, we regard these values to be clearly lower than the normal values as measured by speckle-tracking echocardiography[29
]. Reproducibility was excellent, with ICC of 0.92 and 0.96 for inter- and intra-observer variability, respectively. Several authors have found reduced twist in acute or chronic myocardial ischemia compared with twist in healthy individuals, and twist reduction is correlated to the extent of LV EF reduction[29
]. Twist and the more simplified apical torsion have been suggested as reliable and sensitive tools to detect LV dysfunction. In a patient group of acute LAD myocardial infarction, Han et al. found a positive correlation between LV EF and twist, and in addition twist significantly improved one month after revascularization, parallel to a mean EF increase from 38.8% to 49.7%[33
]. In the present study mean baseline EF was higher. Further studies, also differentiating smaller from larger infarctions, are needed to evaluate potentials and clinical significance for twist development after acute myocardial infarction.
According to the standardized scheme for myocardial territory assignment the LAD artery supplies the anterior wall and the anterior part of the septum, as well as the apical septum and the apical cap[15
]. Ortiz-Pérez et al. have suggested a modification to this scheme, adding the mid anterolateral segment and the apical lateral and inferior segments to the LAD territory[34
]. Individual variation will add complexity to these schemes in any patient studies. In the present study, only patients with their first ST-elevation anterior wall infarction were included. Small, medium-sized and large infarcts were quite evenly represented. The relative lack of basal slice LGE in the small infarcts probably was a consequence of the site for LAD occlusion. In the mid-ventricular slices LGE of the anterior lateral wall and the inferior part of the septum was of similar magnitude, and quite significant. Visually, the LGE areas of these segments were fringes of the LGE in the neighboring LAD territory segments. In the apical slices all segments were largely affected, supporting the modification suggested by Ortiz-Pérez et al.[34
]. As illustrated in Figure average reduction of segmental strain followed a pattern similar to the average LGE involvement, although strain values were relatively lower in the septum.