Cardiac amyloidosis (CA) is a myocardial disease characterized by abnormal extracellular deposition of amyloid fibrils, which gives rise to a progressive structural and functional damage to the cardiac tissue [1, 2]. CA is the main cause of death and occurrence in systemic amyloidosis [3]. On the basis of the underlying nosology, two subtypes (systemic light chain (AL) amyloidosis and transthyretin (ATTR) amyloidosis) account for most cases of cardiac amyloid. The two types of amyloidosis possess different clinical presentations and prognosis [4, 5].

The diagnostic approaches of cardiac amyloidosis include clinical symptoms, laboratory tests, non-invasive imaging, and histopathological diagnosis [6]. Unfortunately, this disease is commonly asymptomatic over a period of time from the beginning and the symptoms are usually nonspecific, and therefore its diagnosis is often delayed [2]. Currently, the gold standard for the diagnosis of CA is endomyocardial biopsy [7]. Nevertheless, endomyocardial biopsy is an invasive modality which can lead to unwanted complications. Echocardiography is widely employed for the diagnosis of CA in patients with suspected amyloidosis in clinical settings, however, it does not differentiate ATTR from AL CA [8]. It is reported that the diagnostic accuracy of echocardiography in combination with electrocardiogram (ECG) findings is only 60% [9]. Cardiac magnetic resonance (CMR) imaging is a mature and advanced imaging approach to describe the morphological characteristics and function of the heart and determine the characteristics of cardiac tissue, however, it may be in lack of specificity in distinguishing the potential causes of different types of CA and holds important prognostic information [5, 10, 11]. Molecular imaging is another type of noninvasive modality for the diagnosis of CA. The favorable efficacy of technetium (Tc)-99m labelled bone seeking tracers in single photon emission computed tomography (SPECT) (pyrophosphate (^99mTc-PYP), 3, 3-diphosphono-1,2-propanodicarboxylic acid (^99mTc-DPD), and hydroxymethylene diphosphonate (^99mTc-HMDP)) for diagnosing CA have been manifested in several studies [12‐14]. Furthermore, positron emission tomography (PET) scans with tracers including ¹¹C-Pittsburgh compound B (PIB), ¹⁸F-florbetapir, ¹⁸F-florbetaben, ¹⁸F-NaF, and ¹⁸F-flutemetamol have been studied for cardiac amyloidosis [15‐18]. Compared to SPECT, PET shows higher spatial resolution and may provide more accurate quantification of absolute tracer uptake [5, 14].

As far as we are concerned, accumulated studies and meta-analyses have evaluated diagnostic performance of non-invasive modalities for the confirmation of CA [12, 19‐23]. Most of these meta-analyses are on single-modality basis. The aim of this study was to generate a more comprehensive comparison of CMR, SPECT, and PET in the identification of CA by pooling the data of available studies, and subsequently to provide updated evidence-based information and hints for not only scientific research but also for the implement and decision-making of clinical practitioners.

This meta-analysis was conducted strictly on the basis of the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) [24]. Details on each procedure of the study were reported as follows.

CA is part of systemic amyloidosis, it’s characterized by the abnormal accumulation of amyloid fibrils within the extracellular of the myocardial tissue [28]. Accurate and timely confirmation of CA is of particular importance because cardiac involvement usually can be lethal [29]. Endomyocardial biopsy remains the gold standard for the detection and evaluation of prognosis of CA [30]. However, it’s an invasive method and introduces potential damage to human body [31, 32]. Among those noninvasive modalities, cardiac ultrasound is widely used, but the diagnostic accuracy is relatively low, and it is clinically used to identify potential patients with CA and further workup should be conducted [33, 34]. It is reported that CMR manifested favorable sensitivity and specificity in the identification of CA regardless of its low cost-effectiveness [10, 35]. The increase in myocardial extracellular volume (ECV) is readily detected by CMR via the Late Gadolinium Enhancement (LGE) test, which demonstrated a sensitivity of 80% and a specificity of 90% in detecting CA [34, 36]. Furthermore, the administration of SPECT scans with ^99mTc-DPD, ^99mTc-PYP, ^99mTc-HMDP revealed promising results [37‐39]. Compared with SPECT, PET showed higher spatial resolution, it has been represented as a promising approach in the field of CA diagnosis [40‐42]. In clinical setting, each single or the combination employment of the above cardiac imaging approaches need to be explained together with the other clinical findings. The imaging techniques not only help to diagnose CA, but also help to estimate the type and the severity of the disease, provide prognostic markers of the disease and monitor the effectiveness of therapy [43]. This meta-analysis is focused on the role of the first of these steps: diagnosis of CA.

Previous meta-analysis commonly focused on single diagnosis tool of CA [19, 21‐23]. We conducted a meta-analysis to directly compare the performance of CMR, SPECT and PET for the diagnosis of CA. The analysis was on the updated articles with respect to study design, type of radiotracers in SPECT and PET scans. This is one of the strengths of this study. It is worth noting 20 of the total 31 articles included in this meta-analysis were published in the years of 2019 and 2020, which indicated that noninvasive diagnostic modalities especially SPECT and PET scans have been extensively investigated. In general, results of this meta-analysis revealed that CMR, SPECT, and PET presented high sensitivity and specificity for the diagnosis of CA. The pooled sensitivity (0.98 [0.94, 0.99]) of SPECT scan was the highest. PET manifested the highest pooled specificity (0.95 [0.85, 0.98]). The AUC values of CMR, SPECT and PET were 0.92 [0.89, 0.94], 0.99 [0.98, 1.00] and 0.95 [0.93, 0.96], respectively. When prospective studies were considered, overall sensitivity of SPECT was still the highest (0.98 [0.90, 0.99]). Interestingly, PET scans showed the highest specificity (0.98 [0.68, 1.00]). On the basis of this difference in results, we can make a preliminary conclusion that the study design could be the source of heterogeneity of enrolled studies. Besides, results manifested ^99mTc-HMDP had the highest sensitivity (0.99 [0.83, 1.00]), ^99mTc-PYPhad the highest pooled specificity (0.95 [0.86, 0.99]). ^99mTc-PYP and ^99mTc-HMDP revealed good diagnostic performance with AUC values of 0.99 [0.98, 1.00] and 0.99 [0.98, 1.00], respectively. As for PET scans, PET studies using ¹¹C-PIB was included in pooled analysis, both the pooled sensitivity and specificity reached more than 0.90, the AUC value of was surprisingly 0.98. One study reported that the sensitivity and specificity of ¹⁸F-florbetaben PET for the detection of CA were 100%, the level of evidence in this study was relatively lower than a meta-analysis, and therefore a possibly pooled analysis of PET scans using ¹⁸F-florbetaben is recommended in the future.

In this meta-analysis, we comprehensively searched the online database to enhance the possibility of retrieving as more eligible studies as we could. Two researchers independently performed the whole process of information extraction under the guidance of the study protocol. Moreover, the heterogeneity across the studies included was assessed using Cochran Q test. In general, there existed significant heterogeneities among studies. The sources of heterogeneity may be attributed to difference in the year of publication, study design (as mentioned above), and patient characteristics. We indented to conduct meta-regression to explore the possible origins of heterogeneity, unfortunately, the numbers of PET and CMR studies were insufficient to complete meta-regression. The underlying sources of heterogeneity would be investigated in further studies. Moreover, results of sensitivity analysis claimed that after omitting individual study one after another, the pooled indicators were robust in this study. The Deek’s funnel plot asymmetry tests for publication bias revealed that there may not be publication bias in the meta-analysis. Despite the existence of heterogeneity, we may conclude based on the pooled results that this analysis could provide evidence-based information for scientific research and practical applications in the process of CA diagnosis. As far as scientific research is concerned, prospective studies and PET radiotracers with higher spatial resolution need to be further investigated on the basis of results of this meta-analysis. Meta-analysis with larger sample-sized and amount of studies are recommended. With regard to applications in clinical settings, decision-making of practitioners in the diagnosis of CA should be made according to technical merit, consideration of cost-effectiveness, and the availability of specific modalities. In order to enhance diagnostic accuracy of CA, if possible, the combination of different diagnostic tools is recommended.