The prognostic value of single photon emission computed tomography (SPECT) myocardial perfusion imaging is independent of left ventricular size

Introduction

Stress single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) continues to be widely used for risk stratification. Part of the reason for this lies in the prognostic value conferred by SPECT MPI and its ability to identify patients at risk major adverse cardiac events (MACE).

In the absence of perfusion or functional abnormalities, a normal SPECT MPI provides a ‘nuclear warranty’—a period of time associated with very low event rates; however, the warranty period is known to vary with several clinical factors including the use of pharmacological vs exercise stress (1), hypertension (2), old age, female sex, and diabetes (3). In addition, to these extrinsic factors, several intrinsic cardiac variables are known to negatively influence the impact of the prognostic value of SPECT MPI such as transient ischemic dilatation (4) and impaired left ventricular ejection fraction (LVEF) (3). However, to date, the effect of cardiac volume on the prognostic value of MPI remains largely unexplored.

Distinct from the well-recognized pathological connotations of left ventricular dilatation, small ventricular volumes pose a theoretical concern in light of the limited resolution of SPECT cameras—it is possible that small perfusion defects in small hearts could be overlooked on SPECT imaging due to partial volume averaging; however, this issue does not appear to have been extensively explored in the literature to date although a few studies have suggested a decrease in diagnostic accuracy (5-7). The goal of this retrospective cohort study was to determine the effect of the rest end diastolic volume (REDV) on the long-term prognosis of patients undergoing SPECT MPI. Since there are systematic sex-specific differences in left ventricular REDV, larger in men than women, analyses were sex-stratified.

Methods

Demographics

St. Boniface Hospital, Winnipeg, Canada, is the cardiac center for the province of Manitoba (population 1.3 million). The study cohort comprised consecutive patients undergoing attenuation-corrected (AC) stress-rest SPECT myocardial imaging for suspected coronary artery disease (CAD) between February 2001 and July 2008 (8). In order to exclude subjects with pathologically dilated left ventricles, subjects with a history of acute myocardial infarction (AMI), congestive heart failure, cardiomyopathy or abnormal rest MPI studies (LVEF <50% and/or abnormal rest MPI) were excluded from the analysis. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by University of Manitoba Health Research Board (No. HS1152, H2010:418) and individual consent for this retrospective analysis was waived.

Stress testing, SPECT imaging and image analysis

We performed ^99mTc-sestamibi or tetrofosmin MPI using conventional rest/stress protocols. Stress imaging used symptom-limited treadmill exercise or dipyridamole infusion with low-level exercise (9). Cardiac images were acquired with dual-detector SPECT cameras equipped with low-energy, high-resolution collimators (Vertex; Philips Medical Systems, Milpitas, CA, USA) and subsequently reconstructed with AutoSPECT and Vantage (Philips Medical Systems). Filtered back-projection with a Butterworth filter was used for the reconstruction (order 10 and cut-off 0.50 for rest MPI, order of 5 and cut-off 0.66 for stress MPI). Gadolinium-153 line-sources (Vantage Pro; Philips Medical Systems, Milpitas, CA, USA) were used to reconstruct AC images incorporating scatter correction and depth-dependent resolution compensation. Image sets without and with AC were available for each study.

Left ventricular segmentation, quality control, and quantitation of LVEF, volumes and global total perfusion deficit (TPD) were performed with automated software (QGS-QPS software, Cedars-Sinai Medical Center, Los Angeles, CA, USA) (8). Researchers at Cedars-Sinai Medical Center blinded to clinical information and outcomes performed the image analyses using de-identified image files. The workflow included automated quality control method with manual adjustment if required (10,11). TPD as a percentage of the myocardium from the stress (sTPD) and rest (rTPD) images was calculated from QPS software. Resting end diastolic volume (REDV) was categorized using sex-specific tertile cutoffs. Stress TPD categories with and without AC were assigned using previously published quartile cutoffs (8).

Clinical information

Manitoba Health maintains computerized databases of physician services and hospitalizations provided to all registered residents. This data repository can to be used to track longitudinal health service utilization for an individual through a unique personal health identification number, anonymized to preserve patient confidentiality. Physician service records include information on the date of service, services provided, and diagnosis, which is coded to a 3-digit International Classification of Disease-9-Clinical Modification (ICD-9-CM) code. Each hospitalization is associated with a discharge summary that includes multiple diagnoses [prior to 2004 up to 16 diagnoses coded with 5-digit ICD-9-CM, from 2004 onwards up to 25 diagnoses coded with International Classification of Diseases-10-Canadian Enhancements (ICD-10-CA)]. Retail pharmacy prescription data for the province are collected through the Drug Programs Information Network (12). The accuracy of these data sources has been established for a wide range of clinical disorders, including cardiovascular disease (13,14).

Statistical analysis

Continuous variables [as mean ± standard deviation (SD)] were compared with Student’s two sample t test. Categorical variables (as frequencies) were compared with Pearson’s chi-square. The relationship between subject outcomes, stress TPD, and LV REDV was examined using Cox regression analysis. Age-adjusted hazard ratios (HRs) for MACE (death, hospitalized AMI, hospitalized unstable angina, late revascularization >90 days) were calculated for TPD quartiles sex-stratified. A stress TPD*REDV interaction term was included. We also estimated age-adjusted HRs per SD increase in TPD stratified by REDV category and sex, and tested for TPD*REDV and TPD*sex interactions. Receiver operator characteristic (ROC) analysis was performed in order to determine the impact of LV size on prognosis. Area under the curve (AUC) was calculated for REDV tertiles with MACE as an outcome. The Bonferroni correction was used to adjust for multiple comparisons. Kaplan-Meier analysis was performed to compare the MACE-free survival fractions for each stress TPD quartile, stratified by sex and REDV tertile. The log-rank test was used to compare survival distributions. Analyses were performed using SPSS for Windows, Version 28.0 (IBM Corp. Armonk, NY, USA).

Results

Information on the analytic cohort (N=2,503 with 965 men and 1,538 women) is summarized in Table 1 stratified by sex and MACE outcome. REDV tertile cutoffs of 62.6 and 79.1 mL were used for women, while 92 and 114 mL were used for men. Stress TPD categories with and without AC were used with lower quartile, median and upper quartile thresholds of 1.9, 5.4, and 14.5 for non-AC sTPD, respectively; 2.8, 7.1, and 15.8 for AC sTPD, respectively. Representative examples of small left ventricles (lowest tertile) with abnormal perfusion are shown in Figure 1 (man with REDV 74 mL, sTPD 25%) and Figure 2 (woman with REDV 41 mL, sTPD 9%).

Figure 1 Man with smallest tertile left ventricle (resting end-diastolic volume 74 mL). He was referred for risk assessment for known coronary artery disease and a positive stress. Treadmill exercise on the Bruce protocol was terminated at 8.5 METS due to anginal chest pain and ECG changes at a heart rate of 114 beats per minute (target 132 beats per minute). Myocardial perfusion imaging demonstrated a large inducible perfusion defect (white arrows) involving the left anterior descending territory (sTPD 25%). Angiography showed multivessel disease and he subsequently underwent coronary artery bypass. TPD, total perfusion deficit; METS, metabolic equivalents; ECG, electrocardiogram; sTPD, stress total perfusion deficit.

Figure 2 Woman with smallest tertile left ventricle (resting end-diastolic volume 41 mL). She was referred for risk assessment for recurrent chest pain after previous coronary artery bypass. Treadmill exercise on the Bruce protocol was terminated at 8.4 METS, achieving 86% maximal age-predicted heart rate without anginal chest pain or ECG changes. Myocardial perfusion imaging demonstrated a moderate-sized inducible perfusion defect (white arrows) involving the inferior wall (sTPD 9%). Angiography showed severe native disease in the right coronary artery, without a good target for percutaneous intervention, and she was managed medically. TPD, total perfusion deficit; METS, metabolic equivalents; ECG, electrocardiogram; sTPD, stress total perfusion deficit.

Outcomes were assessed over an average of 6.4±2.3 years. MACE was observed in 254 (26.3%) of 965 men and 261 (17.0%) of 1,538 women. AUCs in Table 2 show similar stratification for MACE from stress TPD regardless of REDV tertile (all P<0.05). There were no significant differences between sexes, or for AC vs. non-AC data (corresponding ROC curves are provided in Figure S1). Kaplan-Meier curves shown in Figure 3 showed that increasing stress TPD quartile was associated with significantly decreased MACE-free survival for both sexes and all REDV tertiles (all log-rank P values <0.002). Specifically, low stress TPD values were associated with low risk for MACE outcomes independently of REDV tertile.

Figure 3 Kaplan-Meier plots for MACE, according to non-AC sTPD category, stratified by sex and left ventricular REDV tertile. All log-rank P values <0.002. MACE, major adverse cardiac event; LVEDV, left ventricular end diastolic volume; sTPD, stress total perfusion deficit; AC, attenuation-corrected; REDV, resting end diastolic volume.

Age-adjusted HRs for stress TPD and REDV to predict MACE by sex are shown in Table 3. As expected, HRs increased with increasing non-AC TPD severity [quartile 4 versus quartile 1 HR 2.92, 95% confidence interval (CI): 1.90–4.51 in men; 4.77, 95% CI: 2.66–8.54 in women] and AC TPD severity (quartile 4 versus quartile 1 HR 4.34, 95% CI: 2.85–6.61 in men; 3.71, 95% CI: 2.33–3.90 in women). However, REDV tertile showed no association with MACE. Importantly, none of the TPD*REDV interactions were significant when Bonferroni-corrected for multiple comparisons. Age-adjusted HRs per SD increase in TPD stratified by REDV category and sex were significant for all subgroups, without significant TPD*REDV or TPD*sex interactions (Figure 4).

Figure 4 HRs for MACE per SD increase in sTPD, stratified by REDV category and sex, without and with AC. All TPD*REDV and TPD*sex interaction P values were non-significant. HR, hazard ratio; TPD, total perfusion deficit; AC, attenuation-corrected; MACE, major adverse cardiac event; SD, standard deviation; sTPD, stress total perfusion deficit; REDV, rest end diastolic volume.

Discussion

We have shown that, after excluding patients with pathologically dilated left ventricles, REDV had no impact on the prognostic accuracy of SPECT MPI. Left ventricular volume has been shown to be a significant prognostic indicator in certain clinical contexts. It has previously been shown that post-stress end systolic volume provides prognostic information in addition to perfusion in patients undergoing MPI and is known to be a significant predictor of survival in patients following AMI (15,16). Furthermore, it has been shown that abnormal end-diastolic volume response in patients undergoing dobutamine stress-echocardiography is a negative prognostic indicator (17); however, to date, it does not appear that the prognostic significance of the end diagnostic volume in patients undergoing stress MPI has been extensively studied.

Some limitations of this study need to be acknowledged. This was a single-center, retrospective cohort study and is prone to the limitations inherent to this study design. In addition, our imaging studies were acquired on an older gamma camera. However, since modern cameras have superior image resolution and would be less likely to overlook smaller perfusion abnormalities, this would not affect our conclusions. Moreover, our image resolution was clearly sufficient to confirm that stress TPD was strongly predictive of MACE outcomes in both men and women. Although we did not detect a significant interaction (effect modification) between TPD and LV REDV, power to detect subgroup differences may have been limited despite our ability to confirm the ability of TPD to stratify MACE in all subgroups. Reliance on data from a single center may limit the generalizability of our findings. It would be important to validate these findings across diverse demographics and settings using multicenter data.

In conclusion, our results suggest that, excluding patients with pathological dilation of the LV, the nuclear ‘warranty period’ conferred by a normal MPI study is independent of resting end-diastolic volume, and that the prognostic significance of perfusion abnormalities seen on MPI is also unaffected by REDV. Both of these observations can be relevant in patients with smaller hearts in whom it may be suspected that perfusion defects may be missed or underestimated due to the combination of low resolution of SPECT cameras and smaller ventricular volumes.

Acknowledgments

The authors acknowledge the Manitoba Centre for Health Policy for use of data contained in the Population Health Research Data Repository (HIPC 2012/2013-18). The results and conclusions are those of the authors and no official endorsement by the Manitoba Centre for Health Policy, Manitoba Health, Healthy Living, and Seniors, or other data providers is intended or should be inferred.

Funding: This research was supported in part by the National Institutes of Health (NIH) grant (No. R01 HL089765 to P.S.).

Footnote

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-655/coif). P.S. participates in software royalties for QPS software at Cedars-Sinai Medical Center and has received research grant support from Siemens Medical Systems and consulting fees from Synektik SA. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by University of Manitoba Health Research Board (No. HS1152, H2010:418) and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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