To our knowledge, this is the first CZT SPECT study measuring GBPS with LDD stress test in patients with ICM. The main finding of our study is that LDD GBPS allows the assessment of the LV contractile reserve and dyssynchrony changes in patients with ICM and LV dysfunction.
All GBPS parameters showed excellent reproducibility both at rest and stress. LV entropy in the ICM group showed the most significant changes during the stress test. Stress induced decrease in EF was accompanied by a simultaneous increase in entropy (but not PSD and HBW). In normal individuals, represent in present study by the 10 control cases, exercise will lead to an increase in LVEF. In disease, the inability of the heart to decrease the ESV and thus to increase the stroke volume leading to a decrease of the LVEF during exercise is an indicator for the presence and severity of stress induced ischemia [13]. This can also be explained by a decrease in some gene expression in the failing heart (i.e. SERCA2a) [14] or by myocardial remodeling post myocardial infarction [15].
Previous studies have shown that dobutamine stress planar ERNA can be performed in patients with ICM [2, 4]. The planar acquisition technique resulted in an underestimation of the LVEF, particularly in patients with LV systolic dysfunction (LVEF < 35%) and also lacked assessment of the LV dyssynchrony [8, 16]. SPECT ERNA avoids overlapping activity in cardiac chambers. The complete removal of counts from the left atrium resulted in a 7–10% higher LVEF when using SPECT ERNA as compared to LVEF obtained from planar ERNA and thus increased the accuracy of LV function assessment [8, 17].
Performing GBPS on conventional SPECT gamma-cameras takes about 20–30 min (32 frames with 40–60 seconds) per each acquisition [1]. Salimian at al. have applied GBPS with increasing doses of dobutamine using a dual-head gamma camera on a canine model using a 143 min dobutamine infusion and a high administered dose of radiopharmaceutical ~ 1,223 MBq, [Salimian S 2017]. This approach is non-applicable in clinical practice. CZT gamma-cameras allow to reduce the GBPS acquisition time to 8 min [18], 5 min [7] or even 4min [6]. In present study, we applied a 5 min acquisition protocol in combination with the LDD stress test.
Previous studies have demonstrated an excellent reproducibility of the LVEF and volumes obtained with GBPS at rest [19, 20]. SPECT ERNA is a very good tool for the assessment of LV dyssynchrony. Our findings of the stress induced changes in dyssynchrony parameters are similar to those of Boogers et al [21], who used a conventional camera and showed good interrater reproducibility for both PSD and HBW in patients with ICM and LVEF ≤ 35%, ICC of 0.88 and 0.93, respectively. The lower ICC values in comparison to our study may be explained by the presence of large perfusion defects (typical in ICM) resulting in incorrect delineation of the myocardium [22]. GBPS avoids this drawback, since it delineates the blood pool and not the myocardium, resulting in more accurate measurements of volumes and function [23]. Moreover, Jensen et al. [24] reported better reproducibility results for rest GBPS parameters (LVEF and volumes) obtained with a CZT device as compared with Anger cameras (both planar and SPECT). Our study demonstrates reproducible results for all parameters, including dyssynchrony both at rest and stress, using a CZT gamma camera.
GBPS is a widely used imaging technique for assessment of myocardial contractility. This approach has diagnostic and prognostic significance in patients with HF including those with arrhythmia (particularly in CRT candidates) [25], pulmonary embolism [26] and cardiotoxicity [17, 20, 27]. This method was validated on cardiac phantom [28] and showed good correlation with CMR [29] and TTE [25]. However, this approach is not widely used for assessment of CR because of the relatively long study duration and high radiation exposure [8]. The CZT technology allows reducing the radiopharmaceutical dose to perform GBPS by up to 40% when the five minute acquisition protocol is applied or even by up to 50% in case of a 10-minute acquisition [8]. In present study the mean 99mTc- RBC administered dose was of 740 ± 111MBq, which is 40% lower than the dose recommended for stress studies [1], while at the same time image quality is preserved.
Left ventricular cardiac reserve is an index of global inotropic function increasing during both physical exercise and pharmacological stress test (usually with dobutamine), of well-established prognostic value [4, 30]. In patients with HF this parameter is used to assess the likelihood for improvement of the LVEF following treatment, whether medical, surgery [31] or device implantation [4, 30]. CR has been also shown to correlate with the amount of viable myocardium post infarction [32].
The most accepted criterion of preserved CR is a 5% absolute increase in LVEF during stress or a relative increase of 20% from the baseline rest LVEF [30, 32]. In present study the absolute increase in LVEF was of 4.5% (IQR 0; 9) in the ICM group and 14% (IQR 10; 19) in the control group, on average. CR remained unchanged in more than half of the ICM patients.
Clinical value of stress-induced change in mechanical dyssynchrony.
Numerous studies have shown that a high LV mechanical dyssynchrony (MD) value at rest is an independent predictor of all-cause mortality in ICM [14, 33, 34]. Kano et al [14] observed a significant inverse correlation between LV entropy and expression of the SERCA2a mRNA level, which mediates the contraction of cardiomyocytes and the re-entry of Ca2 + from the cytoplasm into the sarcoplasmic reticulum. Lower amounts of SERCA2a mRNA are usually noticed in the human failing heart and its reduction is associated with Ca2+ handling impairment and contractile disorders [35].
Exercise or dobutamine stress test can be used to unmask LV dyssynchrony, which can be absent at rest. Such an approach can help identify high-risk patients [36]. Some studies have reported that patients undergoing CRT stress-induced changes in MD show a better correlation to clinical outcome and long-term survival than MD values at rest [37]. Currently, data regarding changes in MD during stress remain controversial. While some studies, using TTE reported that dyssynchrony is not a dynamic state and does not appear during stress [38, 39], other authors claim different patterns of stress-induced MD changes [40, 41]. Such controversial results may be due to the high variability of TTE [5].
We observed a significant decrease in all dyssynchrony parameters, particularly entropy, during stress-test in both groups of patients and controls, similar to some of previously published results [5, 42, 43].
Interestingly we observed a significant increase in entropy but not PSD and HBW in patients with ICM (n = 9) who showed a drop in LVEF at the dobutamine dose of 15 µg/kg/min. None of the control group subjects showed such a response.. This finding may be due to the fact that ischemia [44, 45] can appear during the stress test as a result of increasing myocardial oxygen demand [13] and could represent an additional sign of the extent of disease, in line with TID index [46].