Abstract
We evaluated the prognostic value of 99mTechnetium-pyrophosphate SPECT (99mTc-PYP-SPECT) in 344 patients with transthyretin amyloid cardiomyopathy (ATTR-CM) receiving transthyretin stabilization therapy. Our primary outcome was all-cause mortality over a median follow-up of 27 months. Multivariable Cox regression analysis showed that National Amyloidosis Center (NAC) stage and New York Heart Association (NYHA) class, but not amyloid burden estimated by 99mTc-PYP-SPECT visual grade, independently predicted mortality. Given our findings, we propose combining 99mTc-PYP visual grading 2 and 3 into a single grade (positive). Amyloid burden measured by quantitative 99mTc-PYP-SPECT may offer prognostic value in ATTR-CM and requires further investigation.
Objective:
The aim of our study was to evaluate the prognostic value of amyloid burden estimated by 99mTechnetium-pyrophosphate SPECT (99mTc-PYP-SPECT) visual grade in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) receiving transthyretin (TTR) stabilization therapy.
Methods:
Our retrospective cohort study included 344 ATTR-CM participants receiving TTR stabilization therapy. 99mTc-PYP-SPECT myocardial uptake was graded as 0, 1, 2 or 3, based on myocardial uptake that was either absent, less than, equal to, or greater than rib uptake, respectively. National Amyloidosis Center (NAC) stage was defined by NTpro-BNP (≤3000 pg/ml) and estimated glomerular filtration rate (≥45 mL/min/1.73m2) levels. The primary outcome was all-cause mortality. Kaplan-Meier survival and multivariable Cox regression analyses were performed.
Results:
Of 344 participants (median age 80 years), 88% were men, and 98% had 99mTc-PYP-SPECT visual grade uptake 2 or 3. 76 participants (22.1%) died during follow-up (median 27 months). In Cox regression analysis adjusted for age, NAC stage, NYHA class, left ventricular (LV) mass index, LV ejection fraction, and 99mTc-PYP-SPECT visual grade, only NAC stage (HR 4.01, p-value <0.001) and NYHA class (HR: 5.22, p-value = 0.011) strongly predicted mortality.
Conclusions:
In patients with ATTR-CM receiving TTR stabilization therapy, organ dysfunction evidenced by NAC stage and NYHA class, but not by amyloid burden on 99mTc-PYP-SPECT visual grade, are strong predictors of mortality. Our results support a revision to 99mTc-PYP visual grading 2 and 3 into a single grade positive. Future work is needed to evaluate whether amyloid burden measured by quantitative 99mTc-PYP-SPECT offers prognostic value in ATTR-CM.
Graphical Abstract
Introduction:
Transthyretin amyloid cardiomyopathy (ATTR-CM) is an important and underrecognized cause of morbidity and mortality in elderly patients(1–3). Transthyretin (TTR) is a tetrameric transport protein produced in the liver and is involved in the transport of thyroxine and retinol. In ATTR-CM, unstable TTR dissociates into monomers, dimers, and oligomers that aggregate into amyloid fibrils, causing heart failure, conduction and valvular disease, neuropathy, and mortality. Tafamidis is a drug that stabilizes TTR tetramers and prevents their dissociation and limiting further amyloid deposition. In the landmark ATTR-ACT randomized controlled trial tafamidis therapy, compared to placebo, significantly reduced mortality and cardiovascular-related hospitalizations. Despite these benefits, approximately 30% of the patients treated with tafamidis in this study died within 30 months of follow-up (4). Patients with New York Heart Association (NYHA) class III symptoms were found to have worse outcomes despite tafamidis therapy. Advanced heart failure from high amyloid burden was proposed as the reason for such increased mortality. However, whether high cardiac amyloid burden estimated by radionuclide methods impacts outcomes in patients treated for ATTR-CM has not been studied.
Cardiac single-photon emission computed tomography (SPECT) using bone-avid tracers [such as 99m-technetium-labeled pyrophosphate (99mTc-PYP), 99mTc-3,3-diphosphono-1,2-pyrophosphare (99mTc-DPD), or 99mTc-hydroxymethylene diphosphonate (99mTc-HDP)] is a well-established technique for the non-invasive diagnosis of ATTR-CM, as long as concurrent plasma cell dyscrasias are excluded (5). In untreated patients with ATTR-CM, high myocardial tracer uptake on semiquantitative visual grading and quantitative heart-to-contralateral ratios portended worse survival (6–9). Furthermore, several markers such as NT-proBNP and outpatient diuretic intensification have been associated with increased risk of mortality in patients with ATTR-CM (10). However, patients diagnosed contemporaneously have a milder disease phenotype and heart failure symptoms despite higher median ages (11, 12), and clinical outcomes are improving over time (13). But, data on the prognostic value of amyloid burden on survival following tafamidis therapy are limited. Therefore, the aim of our study was to evaluate the prognostic value of amyloid burden estimated by 99mTc-PYP-SPECT visual grade in patients with ATTR-CM receiving TTR stabilization therapy using real-world data.
Methods:
Study Population and Design
This retrospective cohort study included 344 consecutive patients evaluated at the Mass General Brigham Amyloidosis Program between March 2019 and April 2024. All patients with confirmed diagnosis of ATTR-CM, who were treated with TTR stabilization therapy (with either tafamidis or diflunisal), and had interpretable bone-avid tracer (PYP) cardiac SPECT images, were systematically included in the study. The diagnosis of cardiac amyloidosis was confirmed either through (1) endomyocardial biopsy demonstrating congophilic deposits with confirmatory immunohistochemistry or mass spectrometry, or (2) a non-invasive clinical diagnosis based on positive cardiac 99mTc-PYP -SPECT (visual grade ≥2) and concurrent exclusion of plasma cell dyscrasias via serum free light chain assay and urine and serum immunofixation electrophoresis analyses.
Clinical evaluation
The institutional Research Patient Data Registry was used to systematically identify all patients who were prescribed tafamidis therapy. Clinical and demographic data, including NYHA functional class, were obtained from electronic medical records at the time of initiation of TTR stabilization therapy. Additionally, all participants were confirmed to have successfully started tafamidis therapy and remained on therapy until the end of the follow-up period.
Laboratory data
N-terminal pro B-type natriuretic peptide (NT-proBNP), estimated glomerular filtration rate (eGFR), and transthyretin levels (prealbumin) were measured within 60 days prior to initiating TTR stabilization therapy. Based on these laboratory results, National Amyloidosis Center (NAC) stages were defined as follows: Stage I , NT-proBNP ≤ 3000 ng/L and eGFR ≥ 45 mL/min/1.73 m2; Stage III, NT-proBNP > 3000 ng/L and eGFR <45 mL/min/1.73 m2; and the remainder were considered to be Stage II (14).
Echocardiography
Echocardiograms performed clinically, with a median interval of 25 days prior to TTR stabilization therapy initiation, were evaluated using commercially available devices (iE33, Philips Medical Systems; and Vivid 7, GE Medical Systems, Milwaukee, WI) with transducer frequencies appropriate for body size and acoustic windows. Imaging and analysis protocols followed the current recommendations of the American Society of Echocardiography and the European Association of Cardiovascular Imaging (ASE/EACVI) (15–17). Standard measures of cardiac structure, as well as systolic and diastolic function, were obtained, including left ventricular (LV) mass index, wall thickness, ejection fraction, global longitudinal strain, and end-diastolic and systolic volumes.
99m-Technetium-labeled-pyrophosphate cardiac SPECT
All participants underwent either 99mTc-PYP SPECT-only or SPECT/CT imaging as part of their routine diagnostic workup for suspected ATTR-CM. A mean activity of 18.7 ± 0.67 mCi of 99mTc-PYP or HDP (at times of PYP shortage) was administered intravenously, and imaging was performed either 1 or 3 hours after tracer administration. Seventy-seven participants (22.4%) underwent SPECT-only imaging, while 267 (77.6%) underwent SPECT/CT. Planar imaging alone or cardiofocal imaging was not used in this study. A single experienced imaging cardiologist reviewed all 99mTc-PYP-SPECT images. Left ventricular myocardial uptake was assessed on SPECT or SPECT/CT images using a semiquantitative visual score: Grade 0 (absent myocardial uptake and normal bone uptake), Grade 1 (myocardial uptake lower than rib uptake), Grade 2 (myocardial uptake equal to rib uptake), and Grade 3 (myocardial uptake greater than rib uptake)(5, 18). For focal on diffuse uptake, the most intense part of the myocardial uptake was used for visual grade assessment. Isolated focal uptake of radiotracer was interpreted as equivocal (grade 1) and further evaluation recommended with cardiac magnetic resonance imaging and or endomyocardial biopsy. Grade 0 and 1 patients included in this study were diagnosed by endomyocardial biopsy (N=7); 1 patient had ATTRv-CM (grade 0) and 6 had wild type ATTR-CM.
Study Endpoints and event ascertainment
The institutional Research Patient Data Registry was used to derive longitudinal follow-up data. The primary outcome was all-cause mortality, which was ascertained by reviewing the participant’s medical records. The end of the follow-up period was defined as the last date of clinical contact or death. Follow-up was completed in 96.8% of the participants and only 11 (3.2%) were lost to follow-up.
Statistical analysis
Statistical analyses were performed using R version 4.3.1 (R Foundation for Statistical Computing, Vienna, Austria). Continuous variables were presented as medians with interquartile ranges (IQR) while categorical variables were summarized as counts followed by percentages (%). The differences among groups were assessed using the Kruskal-Wallis rank sum test for continuous variables, and the χ2 test (or Fisher’s exact test) for categorical variables. Univariable Cox proportional hazards models were created to identify factors associated with time-to-all-cause mortality. Additionally, a multivariable Cox proportional hazards model was created to determine whether the semiquantitative visual score was significantly associated with time-to-all-cause mortality, after controlling for demographic factors, clinical factors, and cardiac biomarkers (age, NYHA classification, NAC stage, left ventricular mass index, left ventricular ejection fraction). These covariates were selected a priori based on clinical plausibility and prior literature (13). Finally, Kaplan-Meier curves were used to estimate survival distribution from time of TTR stabilization therapy initiation. These analyses were stratified by visual score on 99mTc-PYP-SPECT, NAC stage and NYHA classification groups and compared using their log-rank tests. Cox proportional hazards model assumptions were checked by Schoenfeld and deviance residual methods. All p-values were 2-sided with p <0.05 considered to be statistically significant.
Results:
Study population
From the 344 participants included in our study, 88% were men, the median age was 80 years (IQR, 75 – 84), and 87% had wild-type ATTR-CM. Nearly all participants (97%) received TTR stabilization therapy with tafamidis while 2.9 % received diflunisal. All participants remained on stabilization therapy until the end of the follow-up period. Nearly half of the participants (48%) had moderate symptoms (NYHA class II), fewer had severe symptoms (NYHA class III/IV symptoms, 35%), and very few participants had milder class I symptoms (17%). The majority of our cohort had a low risk profile according to the NAC staging system (NAC stage I, 50.6%), and the rest had intermediate (NAC stage II, 31.7%), or high risk (NAC stage III, 17.7%). 99mTc-PYP-SPECT visual grade was most commonly grade 3 (76%) and less commonly < grade 3 (24%). Baseline characteristics stratified by NAC stage are summarized in Table 1. Of note, participants with more advanced NAC stages tended to be older, had a higher proportion of atrial arrhythmias, experienced more severe NYHA class symptoms, and were more likely to have a paced rhythm, received loop diuretics, and be on anticoagulation during their evaluation at the time of TTR stabilization therapy prescription.
Table-1.
Baseline patient characteristics by NAC stage.
| Characteristic | Overall, N = 3441 | Stage I, N = 1741 | Stage II, N = 1091 | Stage III, N = 611 | p-value2 |
|---|---|---|---|---|---|
| Age, years | 80 [75–84] | 79 [73–83] | 80 [77–84] | 82 [78–86] | <0.001 |
| Male sex | 304 (88%) | 156 (90%) | 93 (85%) | 55 (90%) | 0.516 |
| Race | 0.436 | ||||
| White | 301 (88%) | 155 (89%) | 92 (84%) | 54 (89%) | |
| Black | 34 (9.9%) | 15 (8.6%) | 12 (11%) | 7 (11%) | |
| Other | 9 (2.6%) | 4 (2.3%) | 5 (4.6%) | 0 (0%) | |
| Transthyretin type | 0.114 | ||||
| Wild-type | 299 (87%) | 155 (89%) | 94 (86%) | 50 (82%) | |
| Hereditary | 31 (9.0%) | 16 (9.2%) | 10 (9.2%) | 5 (8.2%) | |
| No typification available | 14 (4.1%) | 3 (1.7%) | 5 (4.6%) | 6 (9.8%) | |
| Stabilization therapy | 0.914 | ||||
| Diflunisal | 10 (2.9%) | 6 (3.4%) | 3 (2.8%) | 1 (1.6%) | |
| Tafamidis | 334 (97%) | 168 (97%) | 106 (97%) | 60 (98%) | |
| Coronary artery disease | 203 (59%) | 96 (55%) | 68 (62%) | 39 (64%) | 0.347 |
| Atrial arrhythmias | 283 (82%) | 135 (78%) | 90 (83%) | 58 (95%) | 0.004 |
| Valvular intervention | 45 (13%) | 20 (11%) | 17 (16%) | 8 (13%) | 0.606 |
| Cardiac devices | 0.378 | ||||
| No device | 186 (62%) | 96 (65%) | 56 (59%) | 34 (60%) | |
| Pacemaker | 88 (29%) | 42 (29%) | 26 (27%) | 20 (35%) | |
| Implantable defibrillator (ICD) | 7 (2.3%) | 3 (2.0%) | 4 (4.2%) | 0 (0%) | |
| Cardiac Resynchronization Therapy (CRT) | 18 (6.0%) | 6 (4.1%) | 9 (9.5%) | 3 (5.3%) | |
| NYHA functional class | <0.001 | ||||
| I | 58 (17%) | 43 (25%) | 12 (11%) | 3 (5.0%) | |
| II | 164 (48%) | 83 (48%) | 58 (53%) | 23 (38%) | |
| III | 115 (34%) | 47 (27%) | 35 (32%) | 33 (55%) | |
| IV | 6 (1.7%) | 1 (0.6%) | 4 (3.7%) | 1 (1.7%) | |
| Rhythm at stabilization therapy initiation | <0.001 | ||||
| Sinus | 185 (56%) | 111 (65%) | 55 (53%) | 19 (33%) | |
| Atrial arrhythmia | 107 (32%) | 47 (27%) | 36 (35%) | 24 (42%) | |
| Paced | 41 (12%) | 14 (8.1%) | 13 (13%) | 14 (25%) | |
| Systolic blood pressure, mmHg | 122 [110–135] | 124.5 [110.5–138] | 121.5 [110–130] | 120 [110–130] | 0.257 |
| Diastolic blood pressure, mmHg | 70 [63–78] | 70 [66–78] | 70 [62.8–78] | 70 [61–75.5] | 0.232 |
| Body mass index, kg/m 2 | 26.4 [24.5–29] | 26.8 [24.6–28.9] | 26.6 [24.5–30.1] | 25 [23.2–28.5] | 0.053 |
| NT-proBNP level, ng/L | 2,376 [1,176–4,350] | 1,293 [739–2,074] | 3,470 [2,296–4,719] | 6,682 [4,589–9,369] | <0.001 |
| eGFR, mL/min | 54 [42–70] | 65 [54–78] | 48 [41–61] | 35 [30–40] | <0.001 |
| Prealbumin/transthyretin level, mg/dL | 23 [18–28] | 24 [19–28] | 22[16–28] | 20 [17–25] | 0.034 |
| Medications | |||||
| Beta-blocker | 153 (52%) | 68 (47%) | 55 (59%) | 30 (55%) | 0.181 |
| Loop diuretic | 224 (76%) | 93 (64%) | 82 (87%) | 49 (89%) | <0.001 |
| SGLT2 inhibitor | 40 (14%) | 20 (14%) | 12 (13%) | 8 (15%) | 0.974 |
| ACEi, ARB or ARNi | 93 (32%) | 50 (34%) | 31 (33%) | 12 (22%) | 0.228 |
| MRA | 81 (27%) | 40 (27%) | 26 (28%) | 15 (27%) | >0.999 |
| Anticoagulation | 196 (66%) | 84 (58%) | 67 (71%) | 45 (82%) | 0.002 |
Median [IQR]; n (%).
Fisher’s exact test; Kruskal-Wallis rank sum test.
NT-proBNP = N-terminal pro B-type natriuretic peptide, eGFR = estimated glomerular filtration rate, SGLT2 = Sodium-glucose cotransporter-2, ACEi = Angiotensin-converting enzyme inhibitors, ARB = Angiotensin II receptor blockers, ARNi = Angiotensin II receptor-neprilysin inhibitor, MRA = Mineralocorticoid receptor antagonists
Baseline cardiac phenotype, as assessed by echocardiography and 99mTc-PYP-SPECT visual grade characteristics, stratified by NAC stage are summarized in Table 2. Of note, participants with more advanced NAC stages tended to have a lower global longitudinal strain.
Table-2.
Echocardiographic characteristics and SPECT visual grading.
| Characteristic | Overall, N = 3441 | Stage I, N = 1741 | Stage II, N = 1091 | Stage III, N = 611 | p-value2 |
|---|---|---|---|---|---|
| Echocardiography | |||||
| Left ventricular end-diastolic diameter, mm | 43 [39–47] | 43 [39–47] | 43 [38.5–48] | 42 [39–46.8] | 0.891 |
| Left ventricular end-systolic diameter, mm | 33 [28–37] | 33 [28.5–37] | 33 [28.5–38] | 33 [28–37] | 0.870 |
| Interventricular septum thickness (IVSd), mm | 16 [14–19] | 17 [14–18.5] | 16 [14–18] | 18 [15–20] | 0.106 |
| Posterior wall thickness (PWT), mm | 16 [14–18] | 15 [14–18] | 16 [13–17] | 16 [14–18.8] | 0.188 |
| Left ventricular mass, grams | 279 [236–355] | 276 [240–350] | 276 [230–337] | 299 [241–375] | 0.288 |
| Left ventricular mass index, g/m2 | 143.9 [120.6–174.6] | 142.8 [122–174.2] | 137 [119.6–172] | 157.3 [124.8–191.6] | 0.164 |
| Left ventricular ejection fraction, % | 52 [41–58] | 53 [43–59] | 50 [37–60] | 50 [40–56] | 0.117 |
| Stroke volume, mL | 36 [25–51] | 38 [25–51] | 32 [24–51] | 36 [28–44] | 0.702 |
| Left ventricular end-systolic volume, mL | 50 [39–70] | 48 [38–63] | 55 [42–79] | 48 [39–65] | 0.119 |
| Left ventricular end-diastolic volume, mL | 97 [73–119] | 97 [74–120] | 101 [76–120] | 88 [69–115] | 0.575 |
| Global longitudinal strain, % | −10.5 [−13.3, −8.8] | −11.2 [−13.7, −9.2] | −10.4 [−13, −8.8] | −8.9 [−10.9, −7.9] | 0.012 |
| Relative wall thickness | 0.73 [0.6–0.88] | 0.71 [0.6–0.88] | 0.72 [0.57–0.88] | 0.81 [0.64–0.92] | 0.242 |
| Valvular heart disease | 234 (69%) | 113 (65%) | 75 (70%) | 46 (77%) | 0.258 |
| Aortic valvular disease | 0.268 | ||||
| No aortic valvular disease | 293 (86%) | 153 (88%) | 86 (80%) | 54 (90%) | |
| Moderate aortic regurgitation | 19 (5.6%) | 9 (5.2%) | 7 (6.4%) | 3 (5.0%) | |
| Severe aortic regurgitation | 1 (0.3%) | 0 (0%) | 0 (0%) | 1 (1.7%) | |
| Moderate aortic stenosis | 16 (4.7%) | 7 (4.0%) | 8 (7.5%) | 1 (1.7%) | |
| Severe aortic stenosis | 11 (3.2%) | 4 (2.3%) | 6 (5.6%) | 1 (1.7%) | |
| Mitral valve regurgitation (MR) | 0.595 | ||||
| No MR | 202 (59%) | 107 (62%) | 61 (57%) | 34 (57%) | |
| Moderate MR | 131 (39%) | 64 (37%) | 42 (39%) | 25 (42%) | |
| Severe MR | 7 (2.1%) | 2 (1.2%) | 4 (3.7%) | 1 (1.7%) | |
| Tricuspid valve regurgitation (TR) | 0.137 | ||||
| No TR | 229 (67%) | 125 (72%) | 70 (65%) | 34 (57%) | |
| Moderate TR | 90 (26%) | 39 (23%) | 28 (26%) | 23 (38%) | |
| Severe TR | 21 (6.2%) | 9 (5.2%) | 9 (8.4%) | 3 (5.0%) | |
| SPECT visual grade | >0.999 | ||||
| Grade 0 | 5 (1.5%) | 3 (1.7%) | 1 (0.9%) | 1 (1.6%) | |
| Grade 1 | 3 (0.9%) | 2 (1.1%) | 1 (0.9%) | 0 (0%) | |
| Grade 2 | 76 (22%) | 38 (22%) | 24 (22%) | 14 (23%) | |
| Grade 3 | 260 (76%) | 131 (75%) | 83 (76%) | 46 (75%) | |
Median [IQR]; n (%).
Fisher’s exact test; Kruskal-Wallis rank sum test.
Follow-up
During a median follow-up of 27.4 months (IQR, 16.8–39.4) after initiation of TTR stabilization therapy, 76 participants died (22.1%). The adverse outcomes experienced by our cohort during the study follow-up are summarized in Table 3.
Table-3.
Adverse outcomes during study follow-up.
| Characteristic | Overall, N = 3441 | Stage I, N = 1741 | Stage II, N = 1091 | Stage III, N = 611 | p-value2 |
|---|---|---|---|---|---|
| Death | 76 (22%) | 23 (13%) | 25 (23%) | 28 (46%) | <0.001 |
| Hospice | 38 (13%) | 8 (5.4%) | 12 (13%) | 18 (32%) | <0.001 |
| Cardiovascular hospitalization | 159 (53%) | 67 (46%) | 49 (52%) | 43 (75%) | <0.001 |
| Follow-up duration, months | 27.4 [16.8 – 39.4] | 28 [19 – 40] | 28 [17 – 39] | 22 [11 – 40] | 0.112 |
Median [IQR]; n (%).
Fisher’s exact test; Kruskal-Wallis rank sum test.
Univariable Regression Analysis
On univariable Cox proportional hazard regression analyses, NAC stage (Stage II HR = 1.79, 95% CI = 1.02 – 3.16, p-value = 0.044; Stage III HR = 4.06, 95% CI = 2.34 – 7.06, p-value <0.001, Table 4) and NYHA functional classification (Class II HR = 3.29, 95% CI = 1.00 – 10.9, p-value = 0.051; Class III HR = 7.09, 95% CI = 2.19 – 22.9, p-value = 0.001, and Class IV HR = 32.9, 95% CI = 8.22 – 132, p-value <0.001, Table 4) were strong predictors of mortality. Both showed a graded association with all-cause mortality, where worsening symptom severity and cardiac biomarkers were linked to decreasing survival, as demonstrated by the Kaplan-Meier survival curves (Figure 1 and Figure 2). However, 9mTc-PYP-SPECT visual grade was not a predictor of mortality (Table 4 and Figure-3).
Table-4.
Univariable Cox Proportional Hazards Regressions for all-cause mortality by NAC stage, NYHA functional class, and SPECT visual grade.
| Characteristic | HR1 | 95% CI1 | p-value1 |
|---|---|---|---|
| NAC stage | |||
| Stage I | — | — | |
| Stage II | 1.79 | 1.02 – 3.16 | 0.044 |
| Stage III | 4.06 | 2.34 – 7.06 | <0.001 |
| NYHA functional class | |||
| I | — | — | |
| II | 3.29 | 1.00 – 10.9 | 0.051 |
| III | 7.09 | 2.19 – 22.9 | 0.001 |
| IV | 32.9 | 8.22 – 132 | <0.001 |
| SPECT visual grade | |||
| Grade 0 | — | — | |
| Grade 1 | 1.53 | 0.10 – 24.5 | 0.764 |
| Grade 2 | 1.32 | 0.17 – 9.98 | 0.79 |
| Grade 3 | 1.23 | 0.17 – 8.88 | 0.839 |
HR = Hazard Ratio, CI = Confidence Interval.
Figure-1.
Kaplan-Meier Analysis by NAC stage.
Figure-2.
Kaplan-Meier Analysis by NYHA functional class.
Figure-3.
Kaplan-Meier Analysis by SPECT Visual Grade.
Multivariable Regression Analysis
We performed multivariable Cox proportional hazards regression analysis adjusting for age, NAC stage, NYHA functional class, left ventricular mass index, left ventricular ejection fraction, and 99mTc-PYP-SPECT visual grade. In these analyses, NAC stage and NYHA functional classification remained strong and independent predictors of all-cause mortality (Table 5).
Table-5.
Multivariable Cox Proportional Hazards Regression for all-cause mortality.
| Characteristic | HR1 | 95% CI1 | p-value | q-value2 |
|---|---|---|---|---|
| Age | 0.96 | 0.92 – 1.01 | 0.113 | 0.312 |
| Left ventricular mass index | 1.00 | 0.99 – 1.00 | 0.560 | 0.770 |
| Left ventricular ejection fraction | 0.98 | 0.96 – 1.01 | 0.197 | 0.361 |
| NAC stage | ||||
| Stage I | — | — | — | — |
| Stage II | 1.44 | 0.72 – 2.85 | 0.300 | 0.471 |
| Stage III | 4.01 | 2.05 – 7.82 | <0.001 | <0.001 |
| NYHA functional class | ||||
| I | — | — | — | — |
| II | 2.34 | 0.66 – 8.22 | 0.187 | 0.361 |
| III | 5.22 | 1.47 – 18.6 | 0.011 | 0.040 |
| IV | 102 | 18.5 – 568 | <0.001 | <0.001 |
| SPECT visual grade | ||||
| Grade 0 | — | — | — | — |
| Grade 1 | 1.71 | 0.10 – 29 | 0.708 | 0.858 |
| Grade 2 | 1.22 | 0.14 – 10.5 | 0.858 | 0.858 |
| Grade 3 | 0.82 | 0.10 – 6.56 | 0.853 | 0.858 |
HR = Hazard Ratio, CI = Confidence Interval.
False discovery rate correction for multiple testing.
Discussion:
This retrospective cohort study of 344 patients diagnosed with ATTR-CM and receiving TTR stabilization therapy has revealed 3 key findings. First, we observed that amyloid burden, measured by semiquantitative PYP SPECT visual grade, did not predict all-cause mortality in patients receiving TTR stabilization therapy. Second, disease severity, assessed using NAC staging, is confirmed as a strong and independent predictor of all-cause mortality. Third, NYHA functional classification, which evaluates the degree of heart failure symptoms, was also found to be a strong and independent predictor of mortality.
While 99mTc-PYP-SPECT visual grade is well-established as a reproducible diagnostic tool in patients with suspected ATTR-CM(19), our findings suggest that it may have limited utility in predicting long-term outcomes among treated patients. Our results highlight that the prognostic value of visual Grade 2 and visual Grade 3 is the same in patients receiving TTR stabilizing therapy. Future studies are needed to understand the prognostic implications of change in visual 99mTc-PYP grade. Moreover, future studies should investigate whether advanced quantitation methods for myocardial tracer uptake may provide prognostic insights after the initiation of treatment (20, 21).
Patients with higher NAC stages were more likely to experience worse outcomes, and this relationship persisted even after adjusting for key clinical factors. This finding is consistent with prior literature suggesting that more advanced stages of disease progression are associated with worse survival. Our data reinforce the prognostic value of NAC stage and emphasize its importance as a tool for risk stratification in clinical practice (14).
NYHA class has long been recognized as a reliable indicator of heart failure severity across a variety of cardiac conditions (22, 23). The graded association between worsening NYHA class and mortality in our study suggests that this functional classification remains a robust and easily applicable tool for assessing risk in patients with ATTR-CM receiving stabilization therapy. Hence, NYHA could be considered a metric to be included in future prognostic scores (23).
Implications for Clinical Practice and Research
These findings have important implications for both clinical practice and future research. Notably, these results bring into question whether it is clinically relevant to grade 99mTc-PYP-SPECT into visual grades 0–3. Diagnostically, both visual grades 2 and 3 are considered positive and our study in patients receiving TTR stabilizing therapy suggests that these two grades indicate similar risk. Thus, our study -along with other recent study results (6, 9, 24)- raise a consideration to grade the bone-avid tracer cardiac SPECT scans into three visual grade categories of Grade 0, Grade 1, and Grade 2/3. Additionally, our results suggest that clinicians should prioritize NAC stage and NYHA functional classification for risk stratification and treatment planning. Moreover, the strong prognostic role of these clinical markers supports their inclusion in patient monitoring and decision-making algorithms when evaluating the efficacy of TTR stabilization therapy.
Future research should focus on identifying additional biomarkers or imaging techniques, including amyloid burden measured by quantitative SPECT/CT 99mTc-PYP metrics [or by amyloid Positron Emission Tomography (PET) metrics], that may offer prognostic information beyond what is provided by NAC staging and NYHA classification.
Study Limitations
Our study has several limitations that may affect the generalizability of our results. First, the single health system, retrospective cohort design of our study makes it challenging to fully account for residual confounding, limiting our ability to definitely identify the ideal predictors of mortality. Second, we had a limited number of patients with NYHA class IV symptoms, which limits the precision of our findings in this subgroup. Finally, a large proportion of our cohort did not undergo echocardiographic strain analysis. This is a limitation, as global longitudinal strain has been shown to have prognostic value in cardiac amyloidosis (25). Finally, this study included 99mTc-PYP as well as 99mTc-HMDP studies as well as imaging at 1 hour and at 2–3 hours post injection. We acknowledge 99mTc-PYP and 99mTc-HMDP are distinct radiotracers and the effects of different imaging time points on visual grading and the clinical relevance of these differences remains an area for future research.
Conclusions:
In patients with ATTR-CM who are receiving TTR stabilization therapy, NAC stage and NYHA functional class are strong and independent predictors of all-cause mortality. Despite its powerful role in diagnosis, amyloid burden estimated by 99mTc-PYP-SPECT visual grades 2 and 3 did not demonstrate prognostic value in these patients. Our results support a revision of 99mTc-PYP visual grading 2 and 3 into a single grade positive. Further research is needed to explore additional imaging techniques that may offer prognostic insights, including amyloid burden measured by quantitative 99mTc-PYP-SPECT, amyloid PET metrics, or cardiac MRI.
Acknowledgements:
The authors thank Shawn Murphy and Henry Chueh and the Mass General Brigham Health Care Research Patient Data Registry group for facilitating the use of their database.
Funding:
Romero Pabón: NIH T32 HL 094301.
Clerc: NIH 1K99 HL 175107-01.
Cuddy: NIH 1K23 HL 166686-01; AHA 23CDA857664.
Vijayakumar: NIH T32 HL 094301, Research grant from the Amyloidosis Foundation.
Lan: NIH 5R01HL159987-03, 5R01HL150342-04, and The Brigham Radiology Sundry Account.
Gaggin: None
Di Carli: None
Falk: R01 HL 130563.
Dorbala: R01 HL150342; R01 HL159987; K24 HL157648.
Footnotes
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Conflicts of Interest:
Romero Pabón, Vijayakumar, Lan: None.
Clerc: Research fellowship from the International Society of Amyloidosis and Pfizer.
Cuddy: Investigator-initiated research grant from Pfizer. Consulting fees from Ionis Pharmaceuticals, Astra Zeneca, BridgeBio, and Novo Nordisk.
Gaggin: Research funding from Roche Diagnostics, Pfizer, Alnylam, Akcea, Eidos/BridgeBio. Consulting fees from AstraZeneca, BridgeBio, eMyosound, Merck, Novo Nordisk, Pfizer, TD Cowen. Stock option for Eko; Research payments for clinical endpoint committees from Baim Institute for Clinical Research for Abbott, Siemens, Innolife and Beckman Coulter and from ACI Clinical for Abbott Laboratories and Alexion; in kind support from the HeartShare fellowship; reimbursement/honoraria from Inova Heart and Vascular Institute.
Di Carli: Institutional research funding from Gilead Sciences, Xylocor, Sun Pharma, Intellia Therapeutics, Alnylam, and in-kind research support from Amgen, and consulting fees from MedTrace, Valo Health, IBA, and Sanofi
Falk: Consulting fees from Ionis Pharmaceuticals, Alnylam Pharmaceuticals, Caelum Biosciences. Research funding from GlaxoSmithKline and Akcea.
Dorbala: Consulting fees from Pfizer, GE Health Care, Astra Zeneca, and Novo Nordisk. Investigator-initiated grant from Pfizer, GE Healthcare, Attralus, and Siemens.
Declaration of interests
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:
Ardel J. Romero Pabon reports financial support was provided by National Institutes of Health. Olivier F. Clerc reports financial support was provided by National Institutes of Health. Sarah A. M. Cuddy reports financial support was provided by National Institutes of Health. Shilpa Vijayakumar reports financial support was provided by National Institutes of Health. Shilpa Vijayakumar reports financial support was provided by Amyloidosis Foundation. Zhou Lan reports financial support was provided by National Institutes of Health. Rodney H. Falk reports was provided by National Institutes of Health. Sharmila Dorbala reports financial support was provided by National Institutes of Health. Sharmila Dorbala reports a relationship with Consulting fees from Pfizer, GE Health Care, Astra Zeneca, and Novo Nordisk. Investigator-initiated grant from Pfizer, GE Healthcare, Attralus, and Siemens. that includes: consulting or advisory and funding grants. Olivier F. Clerc reports a relationship with Research fellowship from the International Society of Amyloidosis and Pfizer that includes: funding grants. Sarah A. M. Cuddy reports a relationship with Investigator-initiated research grant from Pfizer. Consulting fees from Ionis Pharmaceuticals, Astra Zeneca, BridgeBio, and Novo Nordisk. that includes: consulting or advisory and funding grants. Hanna K. Gaggin reports a relationship with Research funding from Roche Diagnostics, Pfizer, Alnylam, Akcea, Eidos, BridgeBio. Consulting fees from AstraZeneca, BridgeBio, eMyosound, Merck, Novo Nordisk, Pfizer, TD Cowen. that includes: consulting or advisory and funding grants. Marcelo F. Di Carli reports a relationship with Research grant from Spectrum Dynamics, Amgen, and Gilead. Consulting fees from Sanofi and General Electric. that includes: consulting or advisory and funding grants. Rodney H. Falk reports a relationship with Consulting fees from Ionis Pharmaceuticals, Alnylam Pharmaceuticals, Caelum Biosciences. Research funding from GlaxoSmithKline and Akcea. that includes: consulting or advisory and funding grants. M.D.C and O.F.C currently serve as the Editor-in-Chief and Editorial board member for JNC, respectively. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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