Ana Martinez-Naharro

Background: Transthyretin-lowering therapies target the underlying cause of transthyretin amyloid cardiomyopathy (ATTR-CM), but their effects on myocardial amyloid burden and cardiac remodelling remain incompletely characterized. We evaluated the myocardial effects of sustained transthyretin suppression with eplontersen using serial multiparametric cardiovascular magnetic resonance (CMR). Methods: This CMR study was a pre-specified, international, prospective study embedded within the randomized, placebo-controlled phase 3 CARDIO-TTRansform trial. Participants underwent CMR at baseline and planned assessments at weeks 25, 49, 97, and 140. The primary imaging analysis evaluated longitudinal changes in CMR parameters using mixed models for repeated measures. Myocardial amyloid regression and progression were defined as ≥5 percentage-point decreases and increases in extracellular volume (ECV), respectively. All other patients were considered stable. Results: We enrolled 120 participants with baseline and ≥1 follow-up CMR assessment (eplontersen, n=58; placebo, n=62; mean age, 76.7±6.5 years; 95% male; baseline stabilizer, 12.5%). At week 140 eplontersen resulted in lower ECV, compared with placebo (least-squares mean difference [95% CI], –6.7 percentage points [ –8.7 to –4.7]; P<0.001) and lower native T1 ( –25.9ms [–41.7 to –10.2 ]; P=0.002) and left ventricular mass (–19.1g [–28.0 to –10.2]; P<0.001). Eplontersen also increased left ventricular ejection fraction (+5.1% [1.8–8.3]; P=0.002), right ventricular ejection fraction (+4.6% [0.6–8.7]; P=0.03), and left ventricular global longitudinal, circumferential, and radial strain and right ventricular longitudinal strain (all P<0.05), compared to placebo. At week-140, myocardial amyloid regression occurred in 12.5% receiving eplontersen versus 0% receiving placebo, whereas progression occurred in 12.5% versus 76%, respectively. Conclusions: Sustained transthyretin suppression with eplontersen resulted in substantially lower myocardial ECV and favorable changes in cardiac structure, biventricular systolic function, and myocardial deformation compared with placebo in a cohort of patients mostly not on background stabilizer at baseline. These findings provide randomized evidence that lowering circulating transthyretin modifies myocardial disease progression in ATTR-CM and support serial multiparametric CMR for characterizing myocardial treatment response.

BACKGROUND: Diagnosing cardiac amyloidosis (CA) on echocardiography can be challenging due to the imaging overlap between CA and more prevalent causes of a hypertrophic phenotype. This study sought to (1) evaluate the performance of artificial-intelligence (AI) derived measurements incorporated into the established multiparametric echocardiographic scoring system to detect CA; (2) develop and validate an AI-based deep-learning model for video-based detection of CA on echocardiography. METHODS: The study population comprised 5776 patients (CA, 2756; controls, 3020). The training data set included patients from the UK National Amyloidosis Center and Taiwan MacKay Memorial Hospital (CA, 2241; controls, 2130). External test data sets were obtained from the US Duke University Health System (CA, 334; left ventricular hypertrophy controls, 668) and Japan National Cerebral and Cardiovascular Center (CA, 181; left ventricular hypertrophy controls, 222). RESULTS: The multiparametric echocardiographic score computed using AI-derived measurements achieved an accuracy of 79.5% (sensitivity, 75.4%; specificity, 81.5%) in the United States cohort and 79.7% (sensitivity, 81.6%; specificity, 78.1%) in the Japan cohort. The deep-learning model demonstrated accuracies of 96.2% (sensitivity, 96.8%; specificity, 95.7%) and 95.8% (sensitivity, 97.3%; specificity, 94.3%) in the internal validation and internal test sets, respectively. External validation of the deep-learning model showed accuracies of 87.5% (sensitivity, 86.6%; specificity, 87.9%) in the United States and 88.4% (sensitivity, 92.3%; specificity, 85.3%) in the Japanese cohort. Subgroup analysis demonstrated that the deep-learning model showed robust discrimination of CA from other hypertrophic phenocopies: CA versus hypertension (area under the curve [AUC], 0.92 [95% CI, 0.91–0.94]), CA versus hypertrophic cardiomyopathy (AUC, 0.91 [95% CI, 0.87–0.94]), CA versus aortic stenosis (AUC, 0.93 [95% CI, 0.90–0.95]), CA versus chronic kidney disease (AUC, 0.93 [95% CI, 0.91–0.95]). The deep-learning model was able to classify a greater proportion of patients compared with the AI-derived multiparametric echocardiographic score and achieved superior diagnostic accuracy (AUC, 0.93 [95% CI, 0.91–0.95] versus AUC, 0.88 [95% CI, 0.85–0.90]; P <0.001). CONCLUSIONS: Both the multiparametric echocardiographic score computed from AI-derived measurements and the fully automated deep-learning model can accurately identify patients with CA in globally diverse cohorts, with the deep-learning model providing superior performance.

**Author Listing - Lead/ Submitting Author (we will be communicating with this individual): Name, Institution, City and State where the work was | POSTER

**Author Listing - Lead/ Submitting Author (we will be communicating with this individual): Name, Institution, City and State where the work was | POSTER

**Author Listing - Lead/ Submitting Author (we will be communicating with this individual): Name, Institution, City and State where the work was | POSTER

Amyloidogenic serum free light chains (sFLCs) drive disease progression in AL amyloidosis. Matrix-assisted laser desorption/ionization time of flight mass spectrometry–based FLC assay (FLC-MS) has greater sensitivity than conventional sFLC assays allowing for the detection of serological residual disease. We report the utility of FLC-MS in a large series of patients with AL amyloidosis assessing the impact of FLC-MS negativity after treatment on overall survival (OS) and organ response rates. Serum samples were analyzed using FLC-MS at diagnosis and at 6 and 12 months after treatment. The impact of FLC-MS negativity over standard hematologic responses on survival and organ response was assessed. A total of 487 patients were included; 290 (59%) and 349 (71.5%) had cardiac and renal involvement, respectively. There was 100% concordance between the light chain (LC) fibril type and LC isotype identified by FLC-MS. At 6 and 12 months, 81 (16.6%) and 101 (20.7%) were FLC-MS negative. Of those achieving a conventional hematologic complete response (CR) at 6 and 12 months, 45 (27.7%) and 64 (39%) were FLC-MS negative. At 12 months, median OS for CR + FLC-MS negative was not reached vs 108 months in CR + FLC-MS positive (P = .024). At 12 months, 70% of patients with FLC-MS negativity (vs 50% FLC-MS positive) achieved a cardiac response (P = .015). In a multivariate analysis, FLC-MS negativity at 12 months was an independent predictor of better outcomes. FLC-MS can detect persistent monoclonal light chains in a significant proportion of patients in a conventional hematologic CR. FLC-MS assessment promises to be a new standard for response assessment in AL amyloidosis.

BACKGROUND: Apo AI amyloidosis (AApoAI) and Apo AIV amyloidosis (AApoAIV) are rare but increasingly recognized causes of cardiac amyloidosis (CA). We sought to define the cardiac phenotype in AApoAI and AApoAIV using multimodality imaging. METHODS: We identified all patients with AApoAI and AApoAIV assessed at our center between 2000 and 2021, and 2 cohorts of patients with immunoglobulin light-chain amyloidosis (AL) and transthyretin amyloidosis matched for age, sex, and cardiac involvement. RESULTS: Forty-five patients had AApoAI, 13 (29%) of whom had cardiac involvement, 32 (71%) renal involvement, 28 (62%) splenic involvement, 27 (60%) hepatic involvement, and 7 (16%) laryngeal involvement. AApoAI-CA commonly presented with heart failure (n=8, 62%) or dysphonia (n=7, 54%). The Arg173Pro variant universally caused cardiac and laryngeal involvement (n=7, 100%). AApoAI-CA was associated with right-sided involvement, with a thicker right ventricular free wall (8.6±1.9 versus 6.3±1.3 mm versus 7.7±1.2 mm, P =0.004), greater incidence of tricuspid stenosis (4 [31%] versus 0 [0%] versus 0 [0%], P =0.012) and tricuspid regurgitation (6 [46%] versus 1 [8%] versus 2 [15%], P =0.048) than AL-CA and transthyretin CA. Twenty-one patients had AApoAIV, and cardiac involvement was more common than in AApoAI (15 [71%] versus 13 [29%], P =0.001). AApoAIV-CA most commonly presented with heart failure (n=12, 80%), and a lower median estimated glomerular filtration rate than AL-CA and transthyretin CA (36 mL/[min·1.73 m²] versus 65 mL/[min·1.73 m²] versus 63 mL/[min·1.73 m²], P P =0.003), whereas cardiac uptake on bone scintigraphy was less common in AApoAIV-CA than AApoAI-CA (all grade 1) (14% versus 82%, P 172 and >30 months, respectively), and a lower risk of mortality than matched patients with AL-amyloidosis (AL versus AApoAI: hazard ratio, 4.54 [95% CI, 2.02–10.14]; P P =0.013). CONCLUSIONS: Dysphonia, multisystem involvement, or right-sided cardiac disease should raise suspicion of AApoAI-CA. AApoAIV-CA presents most commonly with heart failure and always displays classical CA imaging features, mimicking common forms of CA. Both AApoAI and AApoAIV are associated with a good prognosis and a lower risk of mortality than matched patients with AL-amyloidosis.