Grogan, Martha

Background Prognostic staging systems in transthyretin amyloid (ATTR) cardiomyopathy were developed before the introduction of disease‐modifying treatment. We therefore evaluated contemporary risk stratification according to different staging systems in patients with ATTR cardiomyopathy. Methods All patients with newly diagnosed ATTR cardiomyopathy and baseline biomarker measurements from 2019 to 2023 were included from Mayo Clinic, Rochester, MN. Prognostic outcomes were calculated with Kaplan–Meier analysis for 3e staging systems in the main analysis: the National Amyloidosis Centre (NAC) staging system; a modified Mayo staging system using hsTNT (high‐sensitivity troponin T) cutoff >65 ng/L; the extended NAC model with a fourth stage (NT‐proBNP [N‐terminal pro‐B‐type natriuretic peptide] >10 000 ng/L). Results The study population consisted of 441 patients with a median age of 76 years, 93% were men, 85% were initiated on tafamidis, and 94% had wild‐type ATTR. Median follow‐up was 3.4 years, and 109 deaths occurred during follow‐up. The 3‐year survival for the Mayo stages were 92.3% (88.7–95.9) for stage I, 71.6% (63.0–81.3) for stage II, and 43.5% (32.4–58.5) for stage III. For the NAC system, 3‐year survival were 92.0% (89.0–95.7), 67.5% (59.0–77.3), and 47.0% (34.7–63.5) for stages I, II, and III, respectively. The 3‐year survival by the extended NAC system was 92.0 (69.0–79.2), 69.0% (60.1–79.2), 53.2% (39.9–70.8) and 34.4% (17.4–68.0) for stages I, II, III, and IV, respectively. Conclusions In a contemporary cohort of patients with ATTR cardiomyopathy, the NAC and modified Mayo staging systems remained equally effective in delineating clinically meaningful prognostic groups, whereas the extended NAC system identified a stage IV subgroup with high mortality.

BACKGROUND: Technetium-based cardiac amyloid radionuclide imaging enables noninvasive diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM), but conventional planar and visual semiquantitative approaches have important limitations. We developed the quantitative 3-dimensional Mayo 3D Score, defined as the ratio of mean left ventricular myocardial radiotracer uptake to right atrial blood-pool uptake using computed tomography (CT)-fused single-photon emission CT (SPECT) volumes of interest, and sought to validate its diagnostic performance against myocardial pathology. METHODS: Consecutive patients who underwent 99m Tc-pyrophosphate SPECT/CT at Mayo Clinic for suspected ATTR-CM between June 2017 and January 2025 with archived myocardial tissue were included. Baseline characteristics, including demographics, echocardiogram, biomarkers, visual semiquantitative, and Mayo 3D Score metrics, were collected. Myocardial specimens underwent histopathologic confirmation of amyloid, with amyloid subtype determination and further semiquantitative grading of amyloid burden and deposition patterns. RESULTS: Among 230 patients (median age, 72 years; 78% male), 107 (47%) had ATTR-CM, of whom 9 had hereditary ATTR-CM. The Mayo 3D Score showed excellent discrimination against pathology (area under the receiver operating characteristic curve, 0.92 [0.88–0.96]), exceeding planar Perugini (0.87 [0.83–0.92]; P =0.006), and heart-to-contralateral lung ratio (0.86 [0.81–0.91]; P =0.004) and comparable to SPECT Perugini (0.90 [0.86–0.94]; P =0.12). A cutoff ≥1.0 yielded 86.0% sensitivity, 92.7% specificity, 91.1% positive predictive value, and 88.4% negative predictive value. Among ATTR-positive cases, the Mayo 3D Score correlated strongly with semiquantitative amyloid burden (Spearman ρ=0.69), was higher in pericellular than nodular deposition patterns ( P <0.001), and was not associated with vascular involvement ( P =0.42). CONCLUSIONS: In patients with suspected ATTR-CM undergoing 99m Tc-pyrophosphate SPECT/CT, the Mayo 3D Score demonstrated superior diagnostic performance compared with planar metrics and comparable to SPECT Perugini, while correlating with myocardial ATTR burden and deposition patterns on pathology. These findings support its integration as a quantitative adjunct within clinical diagnostic ATTR-CM workflows.

BACKGROUND: Guidelines recommend 3-hour cardiac amyloid radionuclide imaging (CARI) for transthyretin amyloid cardiomyopathy. Citing rapid blood clearance of 99m Tc-hydroxymethylene-diphosphonate (HMDP) and efficient laboratory throughput, 1-hour imaging is increasingly practiced despite limited supporting evidence. We sought to compare diagnostic performance and interpreter experience of 1-hour versus 3-hour HMDP-CARI. METHODS: Consecutive patients with suspected transthyretin amyloid cardiomyopathy (n=114) underwent both 1-hour and 3-hour HMDP single photon emission computed tomography (CT)/CT. Two cardiologist-radiologist reader teams, blinded to imaging timepoint (1 versus 3 hours), assessed overall interpretation, single photon emission CT–based Perugini grade, interpretation difficulty, interpreter confidence, and need for CT-fused images for anatomic localization. Discordant, equivocal, and difficult cases were arbitrated by a third tie-breaking team. The myocardial-to-blood-pool radiotracer uptake ratio (3-dimensional Score) was measured as a surrogate of contrast resolution. RESULTS: Interinterpreter agreement was high at both time points (κ≥0.81), with more cases requiring arbitration at 3 hours versus 1 hour (22% versus 13%; P =0.049). Overall interpretation and Perugini grades were concordant between time points in 111/114 (97%) and 106/114 (93%) patients, respectively. Three patients (3%) were negative at 1 hour but equivocal at 3 hours, all of which were clinically ruled out for transthyretin amyloid cardiomyopathy. Interpreter confidence was comparable at both timepoints (97% versus 95%; P =0.317). Compared with 3-hour imaging, contrast resolution was inferior (lower 3-dimensional score, P <0.001) and CT fusion was more frequently needed (57% versus 31%, P <0.001) at 1-hour imaging. CONCLUSIONS: In a prospective, blinded comparison of 1-hour versus 3-hour HMDP-CARI, diagnostic performance and interpreter experience were similar, with readers requesting CT fusion more frequently at 1 hour to optimize myocardial-to-blood pool discrimination.

Abstract Introduction AL amyloidosis is a rare disorder caused by amyloid fibrils produced by clonal plasma cells, leading to serious organ dysfunction. Cardiac involvement is a major risk factor for poor survival. CD38-binding Daratumumab (D) targets plasma cells and, with bortezomib, cyclophosphamide and dexamethasone (VCd) is the only approved regimen for newly diagnosed AL amyloidosis. The ANDROMEDA phase 3 study showed significant improvements in hematologic responses, major organ deterioration progression free survival and overall survival, compared with VCd alone. The AQUARIUS study (NCT05250973) evaluated cardiac safety of different D-VCd schedules and potential cardiac toxicity mitigation strategies. Methods This multicenter, open-label, phase 2 study enrolled 151 newly diagnosed AL amyloidosis patients at 37 sites in 10 countries. Patients enrolled in either Cohort 1 (n=120, cardiac involvement [Mayo 2004 stage II/IIIA], randomized 2:1 to receive D + immediate VCd or D + deferred VCd) or Cohort 2 (n=31, racial or ethnic minorities with ≥1 any organ involvement, treated with D + immediate VCd). Immediate VCd began on Cycle 1, deferred VCd on Cycle 4. The primary safety endpoint was the incidence of cardiac treatment emergent adverse events (TEAEs). Cardiac assessments included HS TroponinT, NT-proBNP, echocardiogram (ECHO), ECG, NYHA, and the 6-minute walk test (6MWT). Clinical cardiac signs and symptoms (S&S) were assessed at baseline and monthly. Selected, clinically relevant grade ≥3 and/or serious cardiac TEAEs were defined as Major Cardiac TEAE and were assessed by an independent adjudication committee for causality. Patients were followed for 12 treatment cycles or 12 months from first dose (if treatment discontinued prior to 12 cycles). Results 142 patients from both cohorts had cardiac involvement and received at least one dose of D + immediate VCd (n=103) or D + deferred VCd (n=39). Baseline characteristics were balanced between the two groups, including Mayo 2004 stage (IIIa: immediate VCd, 35.0%; deferred VCd, 35.9%; II: immediate VCd, 62.1%; deferred VCd, 53.8%). Treatment duration (median: 10.4 months) and proportion completing ≥10 cycles (79% vs 85%) were similar. Serious cardiac TEAEs occurred at similar rates across groups (immediate VCd, 7.8%; deferred VCd, 7.7%). The most common serious cardiac TEAE (MedDRA term) was cardiac failure (immediate VCd, 5.8%; deferred VCd, 2.6%). Two deaths occurred within 60 days of first study treatment, both were in the immediate VCd group, cardiac-related and unrelated to treatment. The immediate VCd group had fewer cardiac TEAEs overall (48.5% vs 61.5%) but experienced them more frequently during Cycles 1-3 than deferred VCd (35.9% vs 28.2%). This trend reversed for Cycles 4-6 (immediate VCd, 17.7%; deferred VCd, 28.9%). Cardiac TEAEs were low for both groups for Cycles 7-9 (immediate VCd, 9.3%; deferred VCd, 12.1%) and Cycles 10-12 (immediate VCd, 7.4%; deferred VCd, 12.1%). Levels of NT-proBNP, HS troponin T, the 6MWT, and overall cardiac S&S improved similarly for both treatment groups. Rate of cardiac TEAEs of any grade was similar for Mayo stage III patients in the two groups (immediate VCd, 73.0%; deferred VCd, 68.8%) whereas for Mayo stage II patients the incidence was higher in the deferred group (35.9% vs 57.1%). Twenty patients (Immediate VCd, 13; deferred VCd, 7) experienced 30 Major Cardiac TEAEs (selected grade ≥3 and/or serious). Adjudicators attributed 28 events primarily to amyloid cardiomyopathy and 2 events primarily to treatment. These 20 patients had higher baseline Mayo stage (IIIa: 70% vs 29.5%) than the remaining patients (n=122), higher baseline median NT-proBNP (4862 ng/L vs 1723 ng/L) and overall S&S score (7.5 vs 4.0). Several ECHO measures were worse at baseline in these 20 patients (notably, median GLS: -8.8% vs -13.7% and E prime lateral: 4.4 cm/s vs 6.1 cm/s) as was 6MWT (median distance: 319 m vs 363 m). Complete Response (CR) rates were similar in both groups: immediate VCd, 62.1%; deferred VCd, 59.0%. Median time to CR was 64 days for the immediate VCd group and 113 days for the deferred VCd group. Conclusion The D-VCd regimen (immediate or deferred) had a manageable safety profile consistent with previous studies. Cardiac TEAEs were similar between regimens, and their emergence correlated with the start of VCd. Major cardiac events were associated with underlying disease and baseline risk factors that are quantifiable and monitorable.

Background Transthyretin amyloid cardiomyopathy (ATTR‐CM) has a specific pathophysiology, with myocardial stiffening and systolic dysfunction only in advanced stages. We aimed to investigate the response to cardiac resynchronization therapy (CRT) in ATTR‐CM compared with heart failure. Methods In this multicenter, observational study, patients with ATTR‐CM receiving CRT (n=101) were matched to patients without amyloid cardiomyopathy by sex, age, and implantation type (CRT with versus without defibrillator versus conduction system pacing, upgrade versus first implant). We evaluated changes in QRS duration and echocardiographic parameters following CRT implantation and at the most recent available assessments. The study end points were all‐cause death alone or combined with heart failure hospitalization. Results Patients with ATTR‐CM (median age, 76 [interquartile range, 72–83] years, 98% men, left ventricular (LV) ejection fraction 30% [26–33]) showed greater QRS shortening after CRT implantation ( P =0.012), but not after a median of around 1 year ( P =0.152). There were no significant differences in the absolute LV ejection fraction changes immediately after implantation (+7 [+2/+10] versus +3 [0/+9] units; P =0.124), or to the last echo ( P =0.796), which was performed after 1.3 years in patients with ATTR‐CM and 2.9 years in patients without amyloid cardiomyopathy. Patients with ATTR‐CM had a shorter survival than controls ( P <0.001 for both end points). Patients with ATTR‐CM experiencing an early improvement in LV ejection fraction had a longer survival (log‐rank, 4.3; P =0.038). Conclusions Following CRT implantation, patients with ATTR‐CM show QRS narrowing and improvement in LV ejection fraction, not different from patients without amyloid cardiomyopathy. Early favorable LV remodeling seems to be associated with a lower risk of all‐cause death.