In this study we demonstrated that a dual modality imaging including a baseline rest transthoracic echocardiogram (TTE) combined with a stress MPS (the ECHO-MPS protocol) showed similar diagnostic accuracy as an established stress-rest MPS (Fig. 2). The ECHO-MPS allowed integration of complementary information available from two established non-invasive imaging modalities used for diagnosis and follow-up of CAD [13, 14]. We compared assessment from ECHO-MPS with similar number and localization of defects in MPS. Notably, the ECHO-MPS showed especially good diagnostic accuracy for large and medium defects, which are clinically important, and we showed that they can be adequately assessed with this new protocol. Therefore, the ECHO-MPS approach allows similarly good prognostication of patients evaluated for CAD to standard stress-rest MPS, which has a confirmed incremental prognostic value [15]. Large pool of data showed before, that when MPS is normal, the prognosis is good, and that overall mortality from adverse cardiac events is low [15]. MPS continues to be recognized as an important modality in the management of patients with chest pain. It has Level 1 Category of Recommendation (LOR) for intermediate-risk patients with acute or chronic chest pain and no known CAD even in the newest AHA/ACC chest pain guidelines [16]. In our small study, but with a median follow-up of 12.9 years, we showed that mortality was in the range of 15%, with 16 deaths recorded in the studied group. Our study’s long-term mortality data in patients with intermediate risk of coronary artery disease align with broader findings from the literature. Some large studies showed mortality rates that could be extrapolated for similar time of follow-up. In the Framingham Heart study, mortality data stratified by age and risk factors, showing that individuals in the 60–69 age group with intermediate risk had a 10-year mortality rate around 15–18% [17]. Large international registry REACH showed high 1-year event rates that accrued almost linearly over time. For patients aged 55–64 with intermediate risk, the mortality rate over a 4-year period was approximately 6–7%. Projecting this over a longer period, similar mortality rates (around 15–20% over 10–12 years) could be expected [18]. However, in their study Duvall et al. showed a low annualized cardiac event rate (< 1%) among 10,609 patients with a normal MPS [19]. Large trials such as the ISCHEMIA trial, demonstrated no substantial difference in outcomes between initial invasive or conservative strategies even in patients with severe ischemia [20, 21]. However, our study did not collect specific therapeutic strategies employed, or detailed patient outcomes. Therefore, we cannot fully explore the impact of these factors on patient prognosis. For our study, we included only patients with no more than intermediate cardiovascular risk, because these patients would be expected to have higher rate of normal rest TTE, compared to high-risk patients. Our study was designed and started before coronary computed tomography angiography (CCTA) was available for a study to include CAD anatomic assessment. However, in the meantime, the role of anatomic imaging techniques has been growing, especially CCTA. But, given their often limited availability, and substantial cost, there is still need for large volume cardiovascular imaging techniques like TTE and MPS. Additionally, our study was performed without accessibility to positron emission technology (PET) technology. PET studies have demonstrated that regulation of coronary blood flow is a complex dynamic phenomenon and coronary flow reserve could be influenced by variations in both maximal vasodilation and resting coronary flow values. In absence of obstructive coronary artery disease, risk factors can determine endothelial dysfunction able to influence both coronary vasodilation and resting coronary tone. In example, myocardial hypertrophy, often associated to hypertension, can determine low resting perfusion values despite normal wall motion [4]. In presence of CAD, PET studies demonstrated resting coronary flow values lower than in normal subjects in regions supplied by not-stenotic coronary arteries and normal regional wall motion [5]. Moreover, some patients may have normal wall motion after myocardial infarction [6]. Our data provide evidence of the safety and efficacy of MPS stress only imaging in patients with normal TTE and provide further reassurance of the MPS rest-image omission. However, we did not assess the MPS stress-only approach. To our knowledge, all studies evaluating a stress-only imaging protocol used some form of attenuation correction (AC). A successful utilization of stress-only imaging requires the application of AC capabilities including hardware and software or CT and post-processing iterative reconstruction that was not available for this study [22, 23]. AC can be especially helpful to discern mild abnormalities suspicious for diaphragmatic or breast attenuation [24]. Without AC attenuation artefacts are commonly observed on stress-only studies with a prevalence of 50–78% [25]. However, increased cost of additional hardware and software for AC preclude it from being available in some centers. In our study we used commercially available post-processing MPS software. Further development in sophisticated software reconstruction methods can improve image quality obtained by standard SPECT cameras, which can be exploited to reduce imaging time or radiation dose without replacement of the system with a new costly scanner [26]. Similarly, newer CZT (Cadmium-Zinc-Telluride) gamma cameras offer several advantages, including enhanced image quality, lower radiation doses, and faster acquisition times. However, their high cost, limited availability, need for specialized training, and technological limitations pose significant challenges to their widespread adoption. When considering the implementation of any of mentioned new technologies, these limitations must be weighed against the potential clinical benefits to determine the best approach for patient care. On the other hand, stress echocardiography is a valuable tool in the non-invasive assessment of coronary artery disease and myocardial function, offering several advantages such as no radiation exposure and real-time imaging. However, stress echocardiography is much more demanding from the operator and interpreter point of view than rest echocardiography. Therefore, its limitations, such as operator dependency, technical challenges, limited acoustic windows, and diagnostic variability, especially without contrast, must be considered when choosing the most appropriate imaging modality for a particular patient. However, it is important to note that the use of advanced instrumentation such as CZT gamma cameras or non-ionizing protocols like stress echocardiography can offer even greater levels of safety by further reducing or eliminating radiation exposure. The selection of the most appropriate imaging modality should consider these factors in conjunction with the specific clinical scenario. We believe that, combining rest echocardiography with stress MPS may help mitigate these limitations. A simple bi-modality approach with ECHO-MPS protocol can help imaging centers with TTE and MPS, but no access to AC or CZT or expert stress echocardiography. Standard stress and rest MPS images are still an important practice in high volume cardiology centers. Some authors suggest that routine stress-rest MPS protocols should be reserved for patients with known CAD and prior MI or LV dysfunction. In this setting it is easier to differentiate reversible from fixed defects, recognize artefacts, transient LV dilatation and stunning. It is also more accurate for left ventricular ejection fraction measurement in cases of imperfect gating. Also, resting MPS can be useful in cases with normal TTE and abnormal stress MPS. MPS can sometimes detect perfusion abnormalities in the setting of microvascular disease, while TTE typically does not detect microvascular disease because it does not cause gross structural changes or significant resting wall motion abnormalities. Resting MPS can be important in an uncommon clinical scenario when a patient having had a MI yet showing normal wall motion on TTE in the affected region. This may potentially occur when the ischemic area is small, subendocardial, rapidly reperfused or if collateral circulation is sufficient to preserve myocardial function despite local occlusion. However, the ECHO-MPS can still provide the opportunity to decrease the amount of radiation used in a routine stress-rest MPS, while preserving the diagnostic power. It can also reduce tracer usage, overall costs, time, improve patient convenience and can potentially increase imaging laboratory volume and efficiency. The necessity of TTE before performing MPS may be seen as limiting factor in settings where access to echocardiography equipment may be limited. However, with the advent of point-of-care ultrasound (POCUS) and the increasing availability of compact, handheld ultrasound devices, the integration of echocardiography into routine practice is becoming more feasible. As these handheld ultrasound devices become more prevalent, future studies could focus on validating the use of POCUS in combination with MPS in diverse clinical settings. This would not only broaden the applicability of our findings but also help establish POCUS as a potential part of cardiac assessment prior to MPS. Therefore, our study can help in further developing imaging strategies. It can also help adapting cardiac imaging to fast evolving handheld technology. Whatever the echocardiographic hardware may be, the ideal candidates for ECHO-MPS imaging are patients with no known coronary artery disease and if CAD is present, without prior history of a myocardial infarction or coronary revascularization procedure [27]. In our study, there were differences between the ECHO-MPS and nuclear readers in 13 patients. Artifacts were noted in MPS studies in all groups. The differences observed between the ECHO-MPS, and nuclear readers appear to be largely due to the presence of artifacts and the subjective interpretation of small and subtle abnormalities. The discrepancies may stem from differences in the sensitivity of the modalities and/or the subjective thresholds of the readers for detecting and reporting the smallest defects. These inconsistencies highlight the challenge of interpreting imaging results in the presence of artifacts, which can mimic or obscure true abnormalities. The differences could therefore be attributed to the varying degrees of impact that these artifacts have on the imaging modalities and the interpretive differences among readers. Despite the challenges, the findings of our study, which demonstrated that a hybrid diagnostic approach using resting TTE and stress MPS (ECHO-MPS) offers comparable accuracy to standard MPS, can potentially be generalized to a broader cardiology patient population. Our study included patients with stable angina and normal LV function, which is representative of a significant subset of patients in general cardiology practice. Potentially, similar diagnostic accuracy could be achieved in a more diverse population. However, further studies involving a broader patient demographic, including those with reduced LV function or other coexisting cardiovascular conditions, would be necessary to fully validate these findings. If confirmed, the adoption of this streamlined approach could enhance diagnostic efficiency and reduce unnecessary imaging in a wider clinical context, thereby optimizing resource utilization and patient care across cardiology practices.

Proposal for a hybrid echocardiography-nuclear assessment (ECHO-MPS) to risk stratify patients with CAD. Abbreviations: MPS, myocardial perfusion scintigraphy; SPECT single photon emission computed tomography; TTE, transthoracic echocardiogram

Based on the results of our study, we suggest that the ECHO-MPS protocol present here can be helpful in cardiovascular testing in large number of patients with CAD. Our study strengthens the concept that even simple cardiac imaging tests tend to be complementary. Careful patient selection, physician and technical local expertise, equipment availability, and patient preference are all important factors to consider for the concept of multimodality, patient first imaging [28].

This is a study performed on a small population of 103 patients, which impacts the validation of ECHO-MPS. A larger cohort would strengthen the validation. However, we believe our study still provides valuable insights into this emerging diagnostic approach. Even with a small cohort we performed a prospective, controlled, single center study, with a mix of male and female patients in a range of ages typically referred for cardiac tests, which can offer clinically relevant information. We designed our study with a focused aim of comparing the results of SPECT and echocardiography imaging modalities. As such, we focused on the imaging modalities and did not collect detailed clinical data. Future studies can expand on our findings by incorporating detailed clinical data to further explore relationship between imaging results and patient characteristics. In our study, although we were able to track mortality over a median follow-up of 12.9 years, we did not plan for detailed survival analysis. As a result, we could not differentiate between cardiovascular and non-cardiovascular deaths, which limits our ability to draw specific conclusions about the relationship between baseline risk factors and mortality outcomes in our cohort. Despite these limitations, the mortality data we report provide some insights into long-term outcomes in a population with intermediate risk of coronary artery disease. We used a clinical standard MPS as a reference test for comparison. Because the number of patients who need interventional assessment was very low, there was no option to include invasive coronary angiography as obligatory verification of coronary disease, and it would be unethical to routinely perform invasive procedures at this stage of assessment. As a consequence of the absence of the coronary anatomy of the studied population, we obtained a comparison between the hybrid ECHO-MPS approach and MPS, but not the relative accuracy of the two protocols in our population. Coronary computed tomography angiography was not available during designing of the study. We did not use echocardiographic contrast, that improve myocardial delineation [29], strain imaging, nor three dimensional echocardiography [30, 31]. Automated artificial intelligence systems to augment imaging analysis and clinical interpretation, such as used recently for imaging stress testing were not existent at the time of the study [32].