a Department of Medicine, Division of Cardiology, Johns Hopkins Hospital, 600 N. Wolfe Street/Blalock 524, Baltimore, MD 21287-0409, USA
b Department of Radiology, Johns Hopkins Hospital, Baltimore, MD, USA
Received January 31, 2004; revised May 10, 2004; accepted June 3, 2004 * Corresponding author. Tel.: +1-410-614-1284; fax: +1-410-614-8222 (E-mail: jlima{at}jhmi.edu).
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Abstract |
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Methods and Results Fourteen dogs underwent 90-min coronary artery occlusion followed by reperfusion. Image acquisition was performed 24 h after reperfusion using three techniques: tagged, first-pass perfusion and delayed-enhancement magnetic resonance imaging (MRI). Systolic circumferential strain and both systolic and diastolic strain rates were calculated in 30 segments/animal. Transmural AMI segments displayed reduced systolic contractility when compared to subendocardial AMI segments (systolic strain=2.5±0.5% versus 6.0±0.9%, P<0.01 and systolic strain rate=0.11±0.12 versus 0.82±0.16 s1, P<0.01), and both exhibited significant systolic and diastolic dysfunction compared to remote. Moreover, AMI segments presenting with microvascular obstruction ("no-reflow") displayed further compromise of systolic and diastolic regional function (P<0.05 for both). Importantly, risk region segments only exhibited diastolic impairment (diastolic strain rate=1.62±0.14 versus 2.99±0.13 s1, P<0.001), but not systolic dysfunction compared to remote 24 h after reperfusion.
Conclusion Reversibly injured regions can demonstrate persistent diastolic dysfunction despite complete systolic functional recovery after reperfused AMI. Moreover, the presence of no-reflow entails profound systolic and diastolic dysfunction. Finally, tagged magnetic resonance imaging (MRI) strain rate analysis provides detailed mechanical characterisation of regions with different degrees of myocardial ischaemic injury.
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Introduction |
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Moreover, ischaemic injury after AMI affects not only systolic but also diastolic function.2 Indeed, it has been demonstrated that the phenomenon of myocardial stunning3,4 has both a systolic and a diastolic component.5 In addition, previous studies have shown that patients presenting with global diastolic dysfunction after AMI have a worse prognosis than those without diastolic impairment and that the prognostic information provided by the diastolic assessment is independent from that derived from the systolic evaluation alone.68 However, initial attempts to quantify regional diastolic function using invasive angiographic studies have been hampered by significant technical complexity and very limited clinical applicability.6,9 Previous studies using radionuclide10 and echocardiographic1113 techniques have addressed the non-invasive assessment of regional diastolic function but, to our knowledge, none have investigated regional diastolic abnormalities after AMI using tagged MRI strain rate analysis.
Myocardial tagged MRI is currently the non-invasive gold standard method for regional systolic functional evaluation.14,15 Diastolic assessment by tagged MRI, however, has been limited to the analysis of LV untwisting in early diastole.16 Using a concept similar to that already used in echocardiography, our group applied the calculation of strain rates for the evaluation of both systolic and diastolic regional function using tagged MRI. Strain rate analysis measures the rate of myocardial contraction and relaxation,17 as opposed to the magnitude of myocardial systolic and diastolic deformation (myocardial strains).
In this experimental study, we used tagged MRI strain rate analysis to evaluate regional systolic and, particularly, regional diastolic function in areas with different degrees of myocardial injury after reperfused AMI. We examined the hypothesis that this analysis would allow us to better characterise and distinguish these ischaemically injured regions.
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Methods |
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MRI protocol
All images were acquired 24 h after reperfusion using a 1.5T Signa CV/i scanner (GE Medical Systems, Waukesha, WI). Tagged images were acquired with an ECG-gated, segmented k-space, fast gradient-echo pulse sequence with spatial modulation of magnetisation to generate a grid tag pattern. Eight contiguous short-axis slices were prescribed to cover the entire LV from base to apex. In order to be able to depict regional diastolic deformation accurately, the protocol was optimised to provide a tagging sequence with high temporal resolution. Imaging parameters were as follows: tag separation 6.5 mm, 28 cm field of view, 8 mm slice thickness, matrix size 256x160, repetition time 5.5 ms, echo time 1.4 ms, flip angle α=12°, temporal resolution 22 ms. The temporal profile of each animal during the acquisition of the tagged MRI dataset is presented in Table 1.
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Radioactive microspheres blood flow analysis
Myocardial blood flow was measured at baseline, during coronary artery occlusion and after reperfusion to determine the areas at risk and the regions of microvascular obstruction. For each measurement 2x106 radioactive microspheres (1516 μm diameter) labeled with 113Sn, 46Sc, 57Co, or 114Ru (New England Nuclear) were injected into the left ventricle while an arterial blood sample was withdrawn. Regional blood flow was then determined using standard techniques. Risk regions and areas with microvascular obstruction were defined as those with regional blood flow <50% of remote during coronary artery occlusion and after reperfusion, respectively.
Data analysis
Images from all data sets were cross-registered using the point of insertion of the right ventricular wall in the LV anteroseptal intersection as an anatomic landmark. For each animal, only five short-axis slices from the tagged MRI dataset were used for regional functional analyses. From the original eight slices acquired, the most apical and most basal slice locations were always excluded. From the remaining six slices, based on DE images, the five consecutive short-axis locations that covered the largest volume of infarcted myocardium were selected for regional functional analyses. Each slice was divided into six segments (30 segments/animal).
Tagged images were analysed quantitatively using the user interactive program Diagnosoft HARP (Diagnosoft Inc, Palo Alto, CA).20 For each phase, Lagrangian circumferential shortening strain was computed at the subendocardial, midwall and subepicardial layers of each segment. Strain rates were obtained from the strain measures by deriving strain by time information. For a given phase "n", the strain rate was calculated as
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For each animal, the 30 myocardial segments were divided into four categories according to the degree of ischaemic injury sustained during coronary occlusion and reperfusion. Transmural infarction segments were defined as those with delayed-enhancement involving ⩾50% of their areas, subendocardial infarction segments as those with involvement of <50% of their areas by delayed-enhancement, and risk region segments as those without any involvement by delayed-enhancement, but with regional blood flow measured by radioactive microspheres <50% of remote during coronary artery occlusion. All other regions were considered remote segments. Moreover, all myocardial infarction segments were further subdivided into those with and without microvascular obstruction.
Statistical analysis
All continuous values are reported as means±SEM. Simple linear regression analysis was used to compare continuous variables in segments with different degrees of ischaemic injury after AMI. The observations were regarded as independent across dogs, but not within dogs (STATA 7.0, College Station, TX). The Huber/White/sandwich estimator of variance was used in order to take into account the correlation within dogs.21 The reproducibility of strain and strain rate measurements were assessed using the method described by Bland and Altman.22 All tests were two-tailed and a value of P<0.05 was considered indicative of statistical significance.
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Results |
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The results reported in the text are derived from midwall analysis. The results from subendocardial and subepicardial analyses are presented in Fig. 2. In addition, the time from R wave to peak systolic strain and peak systolic and diastolic strain rates is presented in Table 2.
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Regional diastolic function
Since the level of noise increases in late cardiac cycle phases due to the phenomenon of tag fading, peak diastolic strain rate could be measured in 339 (81%) of all 420 segments. Segments with AMI, in addition to regional systolic dysfunction, showed significant diastolic impairment, expressed as decreased myocardial relaxation in early diastole (Figs. 2 and 3). Indeed, peak diastolic strain rate was reduced in segments with either transmural or subendocardial infarction when compared to remote (1.26±0.07 s1 and 1.50±0.09 versus 2.99±0.13 s1, P<0.001). Despite their preserved regional systolic contractility, risk region segments also displayed significant regional diastolic dysfunction 24 h after reperfusion (peak diastolic strain rate=1.62±0.14 s1, P<0.001 versus remote) (Fig. 2).
The results obtained from the analysis of LV untwisting in early diastole are presented in Fig. 4. Importantly, these results demonstrate the same pattern of regional diastolic dysfunction in infarcted segments and non-infarcted risk regions described for strain rate analysis (Figs. 2 and 4).
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Reproducibility
Fourteen segments, one for each animal, were randomly selected and both strain and strain rate analyses were repeated by another investigator and by the same investigator at a later time. The mean interobserver and intraobserver differences (bias) and repeatability coefficients (±2SD) are summarised in Table 3.
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Discussion |
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Regional systolic function
The assessment of regional systolic function after AMI by strain quantification has been extensively studied, both in animals14,23,24 and in patients.20,25 In all studies, systolic strain in segments with myocardial infarction was reduced compared to remote, which is in accordance to our findings. In addition, our study demonstrates that segments with transmural infarction have greater depression of systolic strain and strain rate than segments with subendocardial infarction (Fig. 2). We also observed that the presence of microvascular obstruction, a marker of severe ischaemic injury, is related to further impairment of regional systolic contractility, which is in agreement with previous studies.23
In our model, risk region segments represented non-infarcted myocardial areas that were subjected to reversible ischaemic damage. Therefore, our finding that these segments exhibited preserved systolic contractility 24 h after reperfusion should be analysed under the light of the myocardial stunning concept. The phenomenon of myocardial stunning after an ischaemic insult is defined as the mechanical dysfunction that persists after reperfusion despite the absence of irreversible damage and despite return of normal or near-normal perfusion.3,4 The capability of delayed-enhanced MRI to accurately distinguish areas of reversible ischaemic damage from necrotic tissue, combined with the ability of tagged MRI to quantify regional function, makes cardiac MRI examination well-suited for the detailed characterisation of this pathophysiological process. It is important to highlight that, in our model, AMI segments were partially composed of irreversibly injured necrotic tissue, but were also partially composed of non-infarcted but ischaemically injured myocardium (particularly subendocardial infarction segments). The degree of ischaemic injury imposed on the non-infarcted myocardial tissue within these segments was severe enough to result in systolic mechanical dysfunction up to 24 h after reperfusion. The adjacent risk region segments also suffered from ischaemic injury, but not of enough magnitude to cause persistent systolic stunning up to 24 h after the ischaemic insult. Therefore, we believe that our study fits the experimental model of stunning after a partly reversible (no necrosis) plus partly irreversible (some areas of necrosis) episode of regional ischaemia in vivo as described by Kloner et al.3
In a previous study, Croisille et al.,24 reported reduced peak systolic strains in non-infarcted risk region segments when compared to remote regions 48 h after reperfusion. However, that finding was based on radial and maximal principal E1 (greater thickening) strains, and not on circumferential strain as is the case of the present study. When circumferential strain was examined, no difference in regional systolic function was detected between risk region segments and remote areas, which is in accordance with our findings.
The time-to-peak systolic strain and strain rate were significantly higher in segments with transmural AMI than in remote areas. A trend towards higher time-to-peak systolic strain rate was also observed among segments with subendocardial infarction (Table 2). We believe these findings might be related to the phenomenon of post-systolic shortening.26 Indeed, as many as 73% (61/84) of transmural and 56% (42/75) of subendocardial infarction segments only reached peak systolic strain after aortic valve closure. In contrast, only 23% (18/77) of risk region and 22% (34/155) of remote segments displayed peak systolic strain in early diastole. As demonstrated by Skulstad et al.,26 post-systolic shortening can result from two distinct mechanisms: passive recoil or active contraction. Although we believe our finding of post-systolic shortening in segments with transmural infarction is probably related to the first mechanism and reflects only passive recoil, we suspect the finding of post-systolic shortening in subendocardial infarction segments could be the result of active myocardial contraction.
Regional diastolic function
In the present study, using strain rate measured by tagged MRI, we were able to demonstrate that regions that suffered significant ischaemic injury during coronary occlusion and reperfusion displayed persistent regional diastolic impairment. Indeed, AMI segments showed both systolic and diastolic regional dysfunction and these findings are in accordance with previous reports.9,13 By contrast, risk region segments only exhibited diastolic impairment, but not systolic dysfunction 24 h after reperfusion. A previous study by Przyklenk et al.,5 described the concept that the myocardial stunning phenomenon is not limited to regional systolic impairment, but, in fact, also has a diastolic component. Moreover, as suggested in a previous study by Wijns et al.,27 the diastolic component would have a lower ischaemic injury threshold for its occurrence than the systolic component, i.e., regions that suffered lesser degrees of ischaemic injury during coronary artery occlusion, may develop prolonged isolated diastolic dysfunction despite restoration of coronary blood flow and recovery of regional systolic contractility. In that study, brief episodes of coronary artery occlusion (<1 min) were applied and patients were followed for a short period of time after coronary angioplasty. Persistence of diastolic dysfunction was documented for up to 12 min after the ischaemic insult. In our experimental model, a 90-min coronary artery occlusion followed by reperfusion was performed and we were able to evaluate regional contractility and relaxation in a wide range of ischaemic injury levels. Moreover, we demonstrate the persistence of regional diastolic impairment in non-infarcted injured segments for as long as 24 h after the ischaemic episode. However, since we did not follow regional diastolic functional recovery beyond 24 h of reperfusion, we were not able to conclusively define whether this finding constitutes persistence of diastolic stunning (with eventual diastolic functional recovery), or whether this actually constitutes irreversible diastolic functional compromise.
In view of the aforementioned concept that ischaemic injury causes regional diastolic dysfunction, it is intuitive to hypothesise that microvascular obstruction areas are characterised by even greater diastolic functional impairment. In fact, it has been shown that both diastolic dysfunction28 and microvascular obstruction29 are related to increased post-infarct LV remodelling. However, to our knowledge, this is the first study demonstrating a direct relationship between microvascular obstruction and greater post-infarct LV diastolic dysfunction.
Limitations
Due to the phenomenon of tag fading in later phases of the cardiac cycle, the positive strain rate related to atrial contraction ("a" wave strain rate) was not evaluated in this study. In addition, tagging protocols with two breath-holds per slice location, that could potentially generate tags that persist with good signal-to-noise ratio throughout the whole cardiac cycle, such as the C-SPAMM pulse sequence, were not used in the present study.
In order to correlate regional LV functional data with the different contrast-enhancement patterns, each slice was divided into six equal segments. However, some segments might not be uniformly composed of just 1 type of myocardial injury, but, in fact, might constitute a mixture of different types. This could potentially lead to averaging of the data. In fact, since myocardial damage does not respect arbitrary segmentation models, this limitation will also be present in the great majority of studies that related regional LV function and different indexes of regional myocardial damage. Importantly, since we were able to clearly identify the differences between segments from each myocardial injury category, we do not believe this limitation had a significant influence on our overall results.
It is also important to highlight that we only assessed the effect of ischaemic injury on regional LV function up to 24 h after coronary occlusion and reperfusion. Therefore, we did not investigate how regional diastolic function relates to long-term outcomes, such as post-infarct LV remodelling or regional myocardial viability. Further studies are required to address these important questions.
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Conclusions |
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Acknowledgments |
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References |
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