Quantification of myocardial ^99mTc-labeled bisphosphonate uptake with cadmium zinc telluride camera in patients with transthyretin-related cardiac amyloidosis

Transthyretin amyloidosis (ATTR) is an important cause of heart failure with preserved ejection fraction (HFpEF) [1‐3], especially in patients with increased wall thickness [4]. Cardiac planar radionuclide imaging using 99mTc-labeled bone-seeking radiopharmaceuticals may identify cardiac ATTR amyloid deposits, even in the early course of the disease, and is now widely used as a noninvasive diagnostic criterion in patients without detectable monoclonal protein [5, 6].

After the diagnosis, median survival ranges from 25 to 69 months depending on the transthyretin genotype (i.e., hereditary variant or wild-type ATTR) and the stage of the disease [7‐9]. Medical therapy using Tafamidis meglumine, that binds to transthyretin and prevents amyloidogenesis, recently demonstrated a reduction in all-cause mortality and cardiovascular-related hospitalizations, offering new therapeutic perspectives in patients with ATTR cardiac amyloidosis. Several studies demonstrated that a high level of cardiac retention of bone radiopharmaceuticals is associated with a decreased survival in patients with ATTR cardiac amyloidosis [10, 11]. However, there is no standardized method for semi-quantitative assessment of cardiac uptake of bone tracers. Besides the visual assessment proposed by Perugini and colleagues [12] to identify patients with cardiac ATTR, several semi-quantitative methods have been proposed to evaluate patients prognosis, including heart to whole-body (H:WB) retention, heart to contralateral lung (H:CL) uptake ratio, and variation of regional left ventricular tracer uptake [10, 13‐15].

In the context of a new era for medical therapy of ATTR cardiac amyloidosis, there is a need for quantitative approaches that would be useful for diagnosis, assessment of patient prognosis, and also therapeutic response. With the widespread use of cadmium zinc telluride (CZT)-based single-photon emission computed tomography (SPECT) camera, it is now feasible to propose a semi quantitative assessment of a cardiac tracer uptake using either 3D reconstructed acquisition or reprojected planar images [16, 17].

The aim of this study was to compare several indexes of cardiac uptake of bone tracers obtained with CZT SPECT in comparison to conventional planar bone scan acquisition in patients with cardiac ATTR.

The results of this study demonstrated that a 3D semi-quantitative analysis of CZT SPECT is feasible and increases the heart-to-background ratio of ^99mTc-labeled bone seeking tracer uptake compared to bidimensional methods, with a difference between the two methods increasing with the severity of the disease.

Cardiac ATTR is an underdiagnosed disease, more common than previously estimated [2], and that predominantly affects patients in their seventh and eighth decade of life [18]. Echocardiographic and cardiac magnetic resonance imaging patterns are non-specific, demonstrating a left ventricular hypertrophy that is frequently absent in the early phase. Advanced techniques using speckle-tracking imaging may reveal an apical sparing of longitudinal strain that enhances diagnostic accuracy but remain poorly investigated [19]. In addition to left ventricular hypertrophy, cardiac magnetic resonance imaging may show a late gadolinium enhancement, especially within the subendocardium, that increases diagnostic sensitivity [20]. On the other hand, it has been demonstrated that cardiac uptake of bone radiopharmaceuticals can early identify cardiac ATTR and help distinguish transthyretin from light chain cardiac amyloidosis [5, 11, 12, 21]. Consequently, bisphosphonate ([^99mTc]TcDPD, [^99mTc]PyP or [^99mTc]TcHMDP) scintigraphy is now a key feature in the diagnostic algorithm in patients with suspected cardiac ATTR [5, 22].

However, the visual assessment of cardiac uptake according to the widely used Perugini grading failed to predict patient prognosis [23]. Recent data pointed out that the intensity of cardiac uptake is a powerful predictor of poor cardiac outcome [10, 11]. Rapezzi et al. [11] demonstrated that a H:WB ratio of [^99mTc]TcDPD uptake > 7.5 was predictive of major cardiac adverse event. In this study, the calculation of the H:WB ratio required a correction for decay and scan speed and a subtraction of the urinary tract and bladder activity that are potential sources of errors. In a multicenter study, Castano et al. alternatively evaluated ^99mTc-PYP cardiac retention by the H:CL ratio of total counts using planar cardiac imaging and demonstrated an increased 5-year mortality in patients with H:CL ≥ 1.6 [10]. Several other indices have been proposed to quantify the amyloid burden using conventional Anger cameras, including heart/skull ratio, SPECT left ventricle/blood pool ratio, and heart/pelvis and heart/mediastinum ratio [13, 21, 24], demonstrating the lack of standardization of nuclear imaging procedures. In a recent study, Gallini et al. evaluated six different indices obtained from planar whole body imaging using conventional Anger camera. Using ROC curve analysis, the sensitivity of these indices ranged from 89 to 100%, with cutoff values ranging from 1.29 to 3.28. In this study, the heart/whole-body ratios were the most accurate in identifying cardiac amyloidosis [13].

Despite the widespread use of dedicated cardiac CZT cameras, this is the first study comparing the assessment of amyloid load using these cameras in comparison with conventional whole-body bone scan. Planar equivalent images, i.e., planograms, were obtained from SPECT acquisition as previously described [17]. The H:B ratio obtained from planograms were significantly lowers than those obtained from 3D images. The count statistics in heart and background regions in the planograms take into account the projection of every anatomic structure that binds the bone radiopharmaceutical, including the rib cage, the sternum, and the soft tissues [25]. Extra-cardiac uptake, including soft tissue involvement, is not constant and varies according to the stage of the disease [23]. On the other hand, the H:B ratio obtained from 3D reconstructed images reflect the heart retention normalized to the lung uptake, a metric that is not influenced by sternum, rib cage, or muscle uptake that are not included in VOIs. Interestingly, Glaudemans et al. [21] using a conventional Anger SPECT camera found an increased left ventricle-to-blood pool ratio in patients with ATTR and left ventricular hypertrophy that was further increased compared to H:WB ratio (4.6 vs. 2.9). Compared to these previous results, we found relatively higher H:B ratio. A possible explanation is the increased sensitivity of dedicated CZT cameras, with a linear count rate response compared to the non-linear response with a saturation at high count rate observed with conventional Anger cameras [26]. Accordingly, our results demonstrated that the underestimation of cardiac retention by planar techniques increases with the mean value of this retention as assessed by 3D CZT SPECT imaging. In addition, 3D H:B provided a good correlation to myocardial thickness, and 3D analysis was able to demonstrate a right ventricular involvement in 30% of the patients, a condition associated with an increased cardiac retention.

The semi-quantitative analysis of 3D CZT SPECT optimized the assessment of bisphosphonate myocardial uptake compared to 2D methods in patients with cardiac amyloidosis.