Gated SPECT/CT uptake patterns in ATTR-CA: Association with myocardial burden, function and prognosis

doi:10.21203/rs.3.rs-8243972/v1

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Gated SPECT/CT uptake patterns in ATTR-CA: Association with myocardial burden, function and prognosis

https://doi.org/10.21203/rs.3.rs-8243972/v1

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Background

Gated SPECT/CT (gSPECT/CT) offers detailed myocardial radiotracer distribution imaging in cardiac transthyretin amyloidosis (ATTR-CA), but lacks a standardized classification. We aimed to develop and validate a gSPECT/CT-based classification system for ATTR-CA and to explore its correlation with clinical profile, cardiac function, and outcomes.

Methods

We conducted an observational study in 130 patients (76.2% male) with confirmed ATTR-CA who underwent planar [99mTc]Tc-DPD scintigraphy and thoracic gSPECT/CT. Myocardial polar maps were constructed and uptake patterns were classified as septal, waning moon, vault, waxing moon, diffuse, or doughnut. Clinical, echocardiographic and genetic data were compared across patterns. A quantitative parameter—the percentage of affected myocardium—was derived from SPECT segmentation. Statistical analyses included Kruskal–Wallis and Fisher’s exact tests (Monte Carlo simulation).

Results

The proportion of female patients differed significantly among patterns (p = 0.041). Diffuse and doughnut patterns predominated in patients with Perugini grade 3 uptake. Myocardial involvement increased progressively across patterns (47% in septal to 85% in diffuse; p < 0.001). LVEF distribution varied: preserved LVEF was more frequent in the waning moon group, while reduced LVEF predominated in septal and doughnut patterns. Heart failure was more common in diffuse and doughnut groups (p = 0.040), and mortality was highest in waxing moon and diffuse groups (p = 0.047). Genetic variants were detected exclusively in vault, waxing moon and diffuse patterns (p = 0.021).

Conclusions

We propose a novel gSPECT/CT-based classification for ATTR-CA that combines qualitative uptake patterns with quantitative myocardial involvement. This system correlates strongly with sex, LVEF, heart failure, genetic findings and mortality, improving phenotypic characterization and potentially aiding risk stratification.

Gated SPECT/CT

transthyretin cardiac amyloidosis

myocardial uptake patterns

[⁹⁹ᵐTc]Tc-DPD scintigraphy

cardiac imaging

amyloid burden quantification

Cardiac transthyretin amyloidosis (ATTR-CA) results from progressive myocardial deposition of transthyretin fibrils, producing restrictive cardiomyopathy characterized by impaired compliance and evolving systolic dysfunction. Early stages typically present with diastolic impairment and preserved ejection fraction, while advanced disease may involve overt systolic compromise. Atrial infiltration is common and increases the risk of arrhythmias, thromboembolic complications and electromechanical dissociation¹².

Non-invasive imaging plays a central role in the diagnosis and characterization of ATTR-CA. Echocardiography and cardiac MRI provide structural and functional information, while [99mTc]-labelled bisphosphonate scintigraphy offers high diagnostic specificity and has become the cornerstone of non-biopsy diagnosis. The Perugini visual scale (grades 0–3) remains the reference method for evaluating myocardial uptake; however, its semiquantitative nature does not account for spatial heterogeneity or pattern-based differences in radiotracer distribution that may carry clinical significance³⁻⁵.

Hybrid SPECT/CT with attenuation correction enhances quantitative accuracy and enables refined visualization of myocardial tracer localization. Despite these advances, the prognostic value of specific distribution patterns, their relationship with gated functional parameters and their association with disease severity remain incompletely understood⁶⁻⁹. A classification framework that integrates both qualitative and quantitative information derived from SPECT/CT could improve phenotypic characterization and support risk stratification.

In this study, we introduce a gated SPECT/CT–based classification system for ATTR-CA designed to systematically define myocardial uptake phenotypes. We aimed to validate these patterns and evaluate their associations with left ventricular ejection fraction (LVEF), clinical status and major outcomes. This approach seeks to extend the Perugini framework by providing additional imaging biomarkers relevant to disease staging and prognostic assessment in Nuclear Cardiology.

Study population

This prospective observational study included 130 consecutive patients with confirmed ATTR cardiac amyloidosis, defined by [99mTc]Tc-DPD scintigraphy showing Perugini grade ≥ 2 and exclusion of AL amyloidosis through serum and urine immunofixation and serum free light-chain analysis. All imaging studies were performed between January 2022 and December 2023, and clinical follow-up continued until manuscript preparation to assess all-cause mortality. All participants provided written informed consent prior to inclusion.

Patients were stratified by sex, age, Perugini grade (2 vs. 3), and left ventricular ejection fraction (LVEF) derived from transthoracic echocardiography. Additional clinical variables included the presence of TTR gene mutations, heart failure, arrhythmias, neurological involvement attributable to amyloidosis, and aortic stenosis.

Bone scintigraphy and ECG-gated SPECT/CT acquisition

Whole-body planar scintigraphy was performed 180 minutes after intravenous administration of 736–762 MBq of [99mTc]Tc-DPD. All patients underwent thoracic ECG-gated SPECT/CT using an NM/CT 870 DR system (GE Healthcare, Chicago, USA). The CT acquisition was used solely for attenuation correction.

Planar imaging was performed using LEHR collimators at a scan speed of 14 cm/min. Gated SPECT/CT was acquired using a 180° step-and-shoot protocol (120 projections), 3-step frames of 25 s per projection, and 16 frames per cardiac cycle. CT parameters included 120 kV, 205 mA, and a slice thickness of 2.5 mm.

Image processing and classification

Reconstruction of tomographic data was performed using Myovation Evolution (GE Healthcare) with an ordered-subset expectation-maximization (OSEM) algorithm (12 iterations, 10 subsets), including attenuation and scatter correction. Butterworth and Ramp filters were applied. Images were generated in IRACRR format and processed using the Emory Cardiac Toolbox (Emory University, Atlanta, USA) to obtain polar maps.

Based on radiotracer distribution, six predefined uptake patterns were identified (Fig. 1):

Septal: focal septal uptake;

Waning moon: uptake in septal, anterior and inferior walls;

Vault: uptake restricted to the anterior wall;

Waxing moon: uptake in lateral, anterior and inferior walls;

Diffuse: homogeneous uptake across the polar map;

Doughnut: diffuse uptake with relative apical sparing.

Quantitative analysis was performed using QPS/QGS (Cedars-Sinai Medical Center), obtaining the percentage of affected myocardium, defined as the proportion of left ventricular myocardium exhibiting increased radiotracer uptake.

Statistical analysis

Statistical analyses were performed using SPSS Statistics (IBM Corp., Armonk, NY), version 10.1 for macOS. Associations between categorical variables and uptake patterns were evaluated with Fisher’s exact test applied to 2×6 contingency tables. Owing to low expected frequencies in several subgroups, Monte Carlo simulation with 10,000 replicates was systematically applied.

Continuous variables (age, LVEF, percentage of affected myocardium) were compared using the Kruskal–Wallis test due to unequal sample sizes and potential non-normality. A p-value < 0.05 was considered statistically significant.

Clinical and demographic characteristics

A total of 130 patients (76.2% male, 23.8% female) were diagnosed with ATTR-CA based on positive [99mTc]Tc-DPD scintigraphy between January 2022 and December 2023 and were clinically followed until May 2025. Clinical and demographic characteristics are summarized in Table 1.

Table 1
Patient demographics, clinical features, and scintigraphic parameters according to uptake patterns.
		Uptake patterns
Characteristic	All patients	Septal	Waning moon	Vault	Waxing moon	Diffuse	Doughnut	p-value
Number of patients	130 (100%)	14 (10.8%)	24 (18.5%)	8 (6.1%)	16 (12.3%)	30 (23.1%)	38 (29.2%)
Male	99 (76.2%)	12 (85.7%)	21 (87.5%)	8 (100%)	11 (68.8%)	18 (60%)	29 (76.3%)	.041*
Female	31 (23.8%)	2 (14.3%)	3 (12.5%)	0	5 (31.2%)	12 (40%)	9 (23.7%)	.041*
Age (years)	83.8 ± 5.7	85.6 ± 5.5	83.8 ± 6	84.1 ± 4.2	84.7 ± 5.4	82.6 ± 6.4	83.8 ± 5.1	.471
Perugini score grade 2	24 (18.5%)	2 (14.3%)	3 (12.5%)	0	4 (25%)	5 (16.7%)	10 (26.3%)	.211
Perugini score grade 3	106 (81.5%)	12 (85.7%)	21 (87.5%)	8 (100%)	12 (75%)	25 (83.3%)	28 (73.7%)	.211
LVEF (%)	52.9 ± 15.3	47.5 ± 12.1	56.6 ± 12.4	47.6 ± 14.2	53.8 ± 18.8	55.5 ± 17	51.4 ± 13.9	.291
Normal	69 (53.1%)	5 (35.7%)	20 (83.3%)	3 (37.5%)	9 (56.3%)	16 (53.4%)	16 (42.2%)	.022*
Mildly depressed	35 (26.9%)	4 (28.6%)	4 (16.7%)	3 (37.5%)	3 (18.7%)	10 (33.4%)	11 (28.9%)	.699
Moderately-severely depressed	26 (20.0%)	5 (35.7%)	0	2 (25%)	4 (25%)	4 (13.2%)	11 (28.9%)	.046*
% Affected myocardium	70 ± 18.1	47 ± 7.9	64.8 ± 12.6	63.4 ± 9.4%	69 ± 15.8	85.1 ± 13.2	71.7 ± 18.1	< .001*
Clinical features
Genetic mutations	6 (4.6%)	0	0	2 (25%)	1 (6.2%)	3 (10%)	0	.021*
Heart failure	85 (65.4%)	8 (57.1%)	12 (50%)	5 (62.5%)	10 (62.5%)	27 (90%)	23 (60.5%)	.040*
Arrythmia	75 (57.7%)	8 (57.1%)	13 (54.2%)	7 (87.5%)	8 (50%)	17 (56.7%)	22 (57.9%)	.651
Amyloidosis-related neurological involvement	41 (31.5%)	4 (28.6%)	4 (16.7%)	4 (50%)	7 (43.8%)	9 (30%)	13 (34.2%)	.418
Aortic stenosis	20 (15.4%)	3 (21.4%)	2 (8.3%)	1 (12.5%)	4 (25%)	5 (16.7%)	5 (13.2%)	.769
Mortality	13 (10.0%)	0	3 (12.5%)	1 (12.5%)	5 (31.2%)	2 (6.7%)	2 (5.3%)	.047*

Demographic differences across myocardial uptake patterns

Sex distribution varied significantly across the six radiotracer uptake patterns (p = 0.041). Septal, waning moon and vault patterns demonstrated a marked male predominance, with the vault pattern consisting exclusively of men. In contrast, diffuse and waxing moon patterns presented the highest proportions of female patients (40% and 31.2%, respectively), indicating a more balanced sex distribution within these phenotypes (Fig. 2).

Age did not differ significantly among the uptake patterns (p = 0.471).

Radiotracer uptake characteristics

Perugini grade distribution showed a non-significant trend across patterns (p = 0.211). Diffuse and doughnut patterns predominated in patients with Perugini grade 3, whereas septal and waning moon patterns were more common among grade 2 patients. The vault pattern was observed exclusively in grade 3 individuals.

Quantitative assessment of myocardial involvement (% affected myocardium) demonstrated significant differences across patterns (p < 0.001). Septal pattern exhibited the lowest involvement (47.0 ± 7.9%), followed by vault (63.4 ± 9.4%) and waning moon (64.8 ± 12.6%). Higher values were observed in doughnut (71.7 ± 18.1%) and diffuse patterns (85.1 ± 13.2%), with waxing moon showing intermediate involvement (69.0 ± 15.8%).

Left ventricular function

LVEF categories differed across uptake patterns. Normal LVEF (≥ 50%) was distributed unevenly (p = 0.022), occurring most frequently in the waning moon pattern (83.3%). Moderately reduced LVEF (< 40%) also varied significantly (p = 0.046), being more prevalent in septal (35.7%) and doughnut (28.9%) patterns. Mildly reduced LVEF (40–49%) showed no significant differences (p = 0.699).

Clinical manifestations

No significant differences were observed across patterns in the prevalence of arrhythmias (p = 0.651), amyloidosis-related neurological involvement (p = 0.418), or aortic stenosis (p = 0.769).

Conversely, several variables showed statistically significant associations:

Genetic mutations occurred exclusively in vault, waxing moon and diffuse patterns, and were absent in septal, waning moon and doughnut groups (p = 0.021).
Heart failure was more common in diffuse and doughnut patterns (p = 0.040).
Mortality differed significantly across patterns (p = 0.047), occurring predominantly in waxing moon and diffuse patterns and not observed in septal pattern.

The distribution of these findings is presented in Fig. 4.

ATTR-CA encompasses a spectrum of clinical phenotypes, the most characteristic being heart failure with preserved ejection fraction (HFpEF). Other manifestations, including autonomic or sensorineural neuropathy, aortic stenosis, atrial fibrillation and microvascular dysfunction, are also frequently reported. Several studies have demonstrated that these phenotypes correlate with findings on multimodality imaging, with the cardiac-predominant form commonly associated with more pronounced abnormalities on echocardiography, ECG and MRI¹⁰⁻¹³.

The principal contribution of this study is the development of a gated SPECT/CT–based classification system for ATTR-CA that enables stepwise characterization of myocardial radiotracer distribution. This framework overcomes inherent limitations of the traditional visual Perugini grading system and, to our knowledge, represents the first tomographic pattern-based approach described for ATTR-CA, offering potential diagnostic and prognostic utility.

Previous studies evaluating bisphosphonate scintigraphy have primarily focused on uptake intensity and its association with prognosis or echocardiographic parameters such as LVEF, strain or ventricular mass. In contrast, our classification integrates spatial distribution patterns with a broader range of clinical and pathophysiological features, expanding upon prior work¹⁴⁻¹⁵.

Sex-related differences were evident across uptake patterns. Male patients predominantly exhibited phenotypes with greater myocardial involvement, whereas female patients more frequently demonstrated intermediate patterns, reinforcing emerging evidence of sex-specific variability in disease expression and progression¹⁶⁻¹⁷.

Heart failure prevalence differed significantly among patterns. The septal and doughnut patterns demonstrated comparable HF rates despite markedly different extents of amyloid burden, suggesting that strategic localization—rather than solely total burden—plays a key role in functional impairment. Septal involvement, even when focal, may disrupt ventricular synchrony, whereas the doughnut pattern reflects more extensive structural compromise. The diffuse pattern showed the highest HF prevalence despite relatively preserved LVEF, consistent with an HFpEF-like phenotype driven primarily by diastolic dysfunction. These findings extend the conventional Perugini-based stratification by demonstrating that spatial tracer distribution provides additional prognostic information independent of global burden¹⁸⁻¹⁹.

Mortality also varied across patterns, with waxing moon, waning moon and vault patterns showing the highest event rates, supporting previously reported associations between cardiac amyloid burden and adverse outcomes²⁰.

This study also introduces a novel quantitative SPECT parameter—the percentage of affected myocardium—which provides a volumetric assessment of amyloid infiltration beyond traditional planar intensity measures or earlier SPECT quantification approaches. This parameter increased progressively across patterns and showed strong associations with clinical severity and heart failure, underscoring its potential utility as a biomarker of disease burden²¹⁻²⁴.

Taken together, these findings highlight the added value of combining tomographic pattern classification with quantitative metrics to enhance phenotypic characterization and refine risk stratification in patients with ATTR-CA. Nevertheless, several limitations should be considered when interpreting our results. First, both the proposed gSPECT/CT classification and the quantitative parameter “percentage of affected myocardium” require external and multicenter validation, particularly across different scanner platforms, acquisition settings and reconstruction protocols. Second, the single-center design and the limited representation of some uptake patterns restrict generalizability and underscore the need for larger cohorts to confirm these observations. Although such constraints are expected in early-stage imaging biomarker development, the present framework establishes a reproducible basis for future studies, and its strong associations with clinical severity further support its potential utility pending validation against histology and long-term outcomes.

This study demonstrates that gSPECT/CT-derived myocardial uptake patterns are closely associated with distinct clinical phenotypes and functional profiles in ATTR-CA. The proposed classification system reveals meaningful relationships between specific spatial distribution patterns, quantitative myocardial involvement and key clinical outcomes, including heart failure and mortality. By integrating pattern-based interpretation with volumetric burden assessment, this approach provides a more comprehensive evaluation than Perugini grading alone. These findings support the incorporation of tomographic pattern stratification into clinical practice to enhance disease phenotyping and improve prognostic assessment in patients with ATTR-CA.

Ethics approval

The study was conducted in accordance with the Declaration of Helsinki and was approved by the institutional Ethics Committee of our center (reference PI-24-527-C).

Informed consent

Written informed consent was obtained from all participants prior to inclusion in the study.

Conflict of interest

The authors declare that they have no conflicts of interest related to this work.

Funding

No external funding was received for this study.

Data availability

The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.

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You are reading this latest preprint version

Gated SPECT/CT uptake patterns in ATTR-CA: Association with myocardial burden, function and prognosis

Status:

Version 1

Abstract

Background

Methods

Results

Conclusions

Figures

INTRODUCTION

MATERIALS AND METHODS

Study population

Bone scintigraphy and ECG-gated SPECT/CT acquisition

Image processing and classification

Statistical analysis

RESULTS

Clinical and demographic characteristics

Demographic differences across myocardial uptake patterns

Radiotracer uptake characteristics

Left ventricular function

Clinical manifestations

DISCUSSION

CONCLUSION

Declarations

References

Status:

Version 1