Auxiliary ischemic markers, the role of left ventricular dyssynchrony
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Myocardial ischemia due to coronary artery disease (CAD) could be detected with a high sensitivity using available imaging methods. However, even with stress single photon emission tomography (SPECT) myocardial perfusion imaging (MPI) ischemia may not be detected in some patients.
Several indirect parameters have been considered in addition to the perfusion pattern, such as stress-transient ischemic dilation (TID), stress right ventricular perfusion, change (rest-stress) left ventricular ejection fraction (LVEF) and transient segmental wall motion and thickening abnormalities.1
Left ventricular (LV) mechanical contraction synchrony has been proposed as a promising tool for selecting chronic heart failure patients who could respond better to resynchronization therapy.2–4 It has been advocated also as a useful marker for ischemia detection, although the results might be affected by several factors such as tracer selection, timing of stress acquisition (early or delayed) or type of stress employed (exercise or vasodilator).
Gender seems also to affect the results: in a normal Japanese database, males presented greater variation in phase histogram parameters; counts and cardiac size could influence the findings according to the authors.5 Moreover, the type of protocol and its sequence (by instance: one-day, stress first) should also be considered.
The number of frames used for gating (8 vs 16) do not appear to affect the results6; however, conduction abnormalities such as left bundle branch block or pacemaker rhythm alters the measurement. Proper myocardial wall detection is critical for repeatability and reproducibility with automated software, but a careful manual adjustment of the limits, especially at the LV base is often needed.7 Injected activity matters as well in this type of analysis; LV mechanical dyssynchrony indices by phase analysis have more variation and are significantly higher if derived from gated SPECT with low-dose radiotracer.8 In a very recent report, heart rate has also been mentioned as important affecting results; time measurement using QGS phase analysis in milliseconds rather than degrees of the cardiac cycle is preferred in patients with normal perfusion.9
Normal myocardium contracts with a narrow synchrony histogram at rest3; with stress, the histogram becomes narrower, due to more efficient muscular contraction observed better when using exercise and early imaging. This is also detected with Rb-82 positron emission tomography (PET) imaging independent of the resting LVEF.10 Tl-201 SPECT MPI early post-stress acquisition can demonstrate LV mechanical dyssynchrony assessed by phase analysis.11,12 In a study with multi-vessel CAD patients using Tl-201 and dipyridamole, more global and territorial dyssynchrony at early post-stress than at rest was observed.13 A case with severe and extensive CAD using Tl-201 with dipyridamole demonstrated incremental value for ischemic stunning detection.14 In our experience, when using dipyridamole, the delayed acquisition (60 minutes post-tracer injection) makes ischemia detection with phase analysis more difficult, even in cases with significant reversible perfusion defects. We could not find differences between rest and post-stress synchrony in these cases.15 Others have shown that the presence of a large reversible perfusion defect does not alter mechanical dyssynchrony by phase analysis. Comparable information was obtained whether using low- or high-dose radiotracer; the authors obtained their results from 20 patients without perfusion defects and 20 with transient defects employing 1 hour delayed stress acquisition, with exercise in only 30% of their cases.16
Another problematic issue in phase analysis is the method selected to define an abnormal LV mechanical contraction. There are different programs to measure it, such as ECTb Emory Tool Box, QGS, 4DM Corridor and cardioGRAF3,17–19 and several data bases.3,5 It appears that the Tc-99m sestamibi SPECT normal values post exercise are not different from Rb-82 PET dipyridamole ones.20
In the retrospective work presented in the current issue of the Journal, Camilletti et al provide new information regarding LV ischemia detection through myocardial stunning using phase analysis. Their perfusion SPECT images were acquired early post-exercise. They evaluated two groups: normal (no ischemia) and ischemia patients excluding those with SDS 1 to 5 as well as those with scar, in order to measure the extent of the ischemia and possible stunning. LV synchrony was compared with wall motion assessed visually and their gold standard was the perfusion status. Their results are in agreement with a similar recent publication using sestamibi with acquisition at 15 minutes post-exercise injection. The authors found that baseline differences in LV volumes and degree of intraventricular dyssynchrony were associated with inducible ischemia and increasing histogram bandwidth (BW).21 Exercise SPECT synchrony analysis was also shown to increase multivessel CAD detection when combining phase standard deviation (SD), TID ratio and perfusion summed stress score (SSS) compared with TID ratio and SSS alone.22
It is interesting to point out that ischemic dyssynchrony has been observed as well with stress dynamic PET with Rb-82 PET using regadenoson;23 in normal MPI, with similar method, the indices are smaller at peak stress vs. rest, independently of LVEF at rest.10 Coronary steal described with vasodilators probably do not produce real stunning as observed with exercise or it may last for a shorter period. Visual wall motion measurement is also difficult; in a prior study by our group employing first pass technique and using sestamibi dipyridamole-isometric exercise, wall motion abnormalities were not helpful in the assessment of CAD.24 A recent work on systolic wall thickening,25 described better correlation with ischemia than LVEF changes, when performing a 2 days exercise protocol with a Tc-99m tetrofosmin and delayed acquisition. Wall thickening-summed difference score quantified the stunning phenomenon, being an independent parameter with the strongest correlation observed with the degree of ischemia and reversible systolic dysfunction. In a later work26; the same group published that systolic thickening with dipyridamole also showed better correlation with the degree of ischemia than with global LV function allowing a better identification of the stunning phenomenon.
Camilletti et al mention in their work that both dyssynchrony and wall motion abnormalities using exercise stress are of great value as auxiliary markers for CAD detection. However, their results like other observations demonstrate that LV wall motion is not very sensitive and that dyssynchrony is a better marker. Possibly both parameters together could be helpful considering automated motion measurement instead of visual wall analysis. In their investigation, there was not a classical gold standard available (coronary angiography) or ideally absolute myocardial flow measurement.
LV dyssynchrony evaluated by phase analysis with gated MPI may provide a good prognostic value. This was demonstrated in end-stage renal disease patients as part of their renal transplant evaluation even beyond information provided by myocardial perfusion and LVEF as predictors of all-cause mortality.27 After adjusting for demographics, co-morbidities, LVEF, and perfusion pattern, phase analysis parameters, particularly phase BW, was independently associated with worse outcome. In that large study, exercise and vasodilator stress (adenosine) were employed and phase parameters analyzed from a stress phase acquired at rest, according to the authors. On the other hand, significant mechanical dyssynchrony have been found in gated SPECT MPI with stronger association with global and cardiovascular mortality compared with electrical dyssynchrony measured with QRS duration.28
In summary, more studies are warranted to confirm that phase analysis can add significant value over other parameters of LV perfusion and function to detect ischemia using gated SPECT MPI. This could also be important in more vulnerable population such as diabetics with cardiovascular risk factors with possible silent ischemia; cases with negative stress MPI or in those with normal stress perfusion SPECT representing balanced three-vessel disease with diffuse stunning. However, some authors believe that synchrony parameters have value only in the presence of reversible perfusion defects.29 Moreover, phase analysis could be more helpful in the group with doubtful, mild or equivocal LV ischemia (including those cases not incorporated in Camilletti’s work with SSS < 5 or those with mild SDS values not considered significant). A larger sample of patients with clinical follow-up and a robust gold standard for myocardial ischemia is still missing in this important subject. We believe that the additional value of phase analysis technique in ischemia detection and its prognostic value to assess intraventricular contraction with diverse stress modalities should be confirmed further when using MPI with Tc-99m tracers.
The author has no conflict of interest to disclose.
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