Ruberg, Frederick L.

Background Radionuclide SPECT/computed tomography (CT) is standard for diagnosing transthyretin cardiac amyloidosis (ATTR-CM), but the prognostic value of quantitative metrics remains incompletely defined. We investigated their prognostic utility and additive value beyond existing staging systems. Methods Retrospective study of patients undergoing technetium-99m-pyrophosphate (PYP) SPECT/CT, including consecutive clinically referred patients (October 2023 to 2024) and trial participants with positive scans from January 2022. Myocardial PYP was quantified using standardized uptake values (SUV mean and SUV max ) and volumetric measures [percent injected dose (%ID), cardiac amyloid activity (CAA)]. Major adverse cardiovascular events (MACEs) comprised heart failure hospitalization or death. Cox and Kaplan–Meier analyses assessed associations; likelihood ratio testing and change in area under the curve (AUC) evaluated the additive prognostic value to existing staging systems. Results Among 43 patients with ATTR-CM, 16 experienced MACE over a median 518 days. AUCs ranged from 0.74 to 0.88 at 3 months and 0.56–0.62 at 12 months. All variables trended toward association with MACE: SUV mean ( P = 0.02), SUV max ( P = 0.03), %ID ( P = 0.06), and CAA ( P = 0.06). After age adjustment, cut-points for SUV max (5.8) and SUV mean (3.5) remained associated with MACE. Adding imaging variables to the National Amyloidosis Centre and Columbia staging systems did not significantly improve prognostic accuracy (Δ χ 2 : 0.40–2.48, P = 0.11–0.53). Interobserver reproducibility was high (intraclass correlation coefficients = 0.89–0.99). Conclusion Quantitative Tc-99m–PYP SPECT/CT metrics were associated with short-term outcomes in ATTR-CM, but did not improve established staging systems. Findings are hypothesis-generating and require validation in larger cohorts.

Importance Transthyretin amyloid cardiomyopathy (ATTR-CM), a progressive disease caused by misfolded transthyretin (TTR), occurs as wild-type (ATTRwt-CM) or variant (ATTRv-CM) forms. p.Val142Ile is the most common variant in the US, linked to rapid progression and increased mortality. Acoramidis achieves near-complete (≥90%) TTR stabilization and showed clinical benefit in the 30-month ATTRibute-CM trial and through month 42 in the ongoing open-label extension (OLE). Objective To evaluate the efficacy of acoramidis in ATTRwt-CM, ATTRv-CM, and variant subgroups (p.Val142Ile and non-p.Val142Ile). Design, Setting, and Participants This international, multicenter, phase 3, randomized placebo-controlled study took place from April 2019 to May 2023 with ongoing OLE (month 42). ATTRibute-CM enrolled 632 participants with ATTR-CM; 611 of 632 were included in the modified intention-to-treat (mITT) population. There were 380 participants who continued into the OLE. These data were analyzed from January 2025 to July 2025. Interventions Oral acoramidis, 712 mg, or placebo twice daily for 30 months, followed by 12 months of open-label treatment. Main Outcomes and Measures All-cause mortality (ACM), cardiovascular-related hospitalizations (CVH), serum TTR, 6-minute walk distance, Kansas City Cardiomyopathy Questionnaire Overall Summary score, and N-terminal pro B-type natriuretic peptide in participants with ATTRwt-CM and ATTRv-CM. Post-hoc analyses were conducted in variant subgroups, including p.Val142Ile. Results Overall, 552 participants with wild-type ATTR-CM (mean [SD] age, 78 [6.3] years; 92.0% male and 8.0% female) and 59 participants with variant ATTR-CM (mean [SD] age, 73 [7.7] years; 77.3% male and 22.7% female) were randomized (mITT population), including 35 with p.Val142Ile. Consistent efficacy was observed in wild-type and variant subgroups for ACM/CVH through month 30 and ACM through month 42. At month 30, acoramidis reduced the risk of ACM/first CVH vs placebo by 31% in ATTRwt-CM (hazard ratio [HR], 0.69; 95% CI, 0.52-0.90; P = .007) and by 59% in ATTRv-CM (HR, 0.41; 95% CI, 0.21-0.81; P = .01). ACM was reduced through month 42 with HRs of 0.70 (95% CI, 0.50-0.98; P = .04) and 0.41 (95% CI, 0.19-0.93; P = .03) in the ATTRwt-CM and ATTRv-CM groups, respectively. Consistent treatment benefit was observed in participants with ATTRwt-CM and ATTRv-CM for secondary end points. Within variant subgroups (p.Val142Ile vs non-p.Val142Ile), consistent treatment benefits were observed for ACM/CVH through month 30 and ACM through month 42. Conclusions and Relevance The beneficial effect of acoramidis was observed consistently in ATTRwt-CM and ATTRv-CM groups. These hypothesis-generating results indicate that further studies are warranted to better characterize the therapeutic benefit of acoramidis in variant subgroups. Trial Registration ClinicalTrials.gov Identifiers: NCT03860935 ; NCT04988386

Introduction: Patients with transthyretin amyloid cardiomyopathy (ATTR-CM) typically have low serum transthyretin (sTTR) levels, worsening heart failure, and increased mortality. A recent study has shown the association of sTTR levels ≥20mg/dL with reduced risk of all-cause mortality and cardiovascular mortality (CVM). It has also been shown that regardless of baseline sTTR level, greater increases in sTTR levels are associated with greater improvements in cardiovascular outcomes. Acoramidis, a near-complete (≥90%) TTR stabilizer, demonstrated a rapid and sustained increase from baseline in sTTR by Day 28 and reduced risk of cardiovascular outcomes in patients with ATTR-CM. Hypothesis: Acoramidis-mediated early increase in sTTR levels ≥20 mg/dL (lower limit of normal) at Day 28 reduces risks of CVM and cardiovascular-related hospitalizations (CVH) in patients with ATTR-CM. Methods: Analyses were conducted in the ATTRibute-CM modified intention-to-treat (mITT) population (acoramidis: 409; placebo: 202). The sTTR concentrations (normal range is 20-40 mg/dL) were assessed using an immunoturbidimetric method (Abbott ARCHITECT system) in a central laboratory. The proportion of participants with sTTR levels below normal at baseline and Day 28 were determined. The relationship between sTTR levels <20 or ≥20 mg/dL, at Day 28 across the pooled acoramidis and placebo treatment groups, and subsequent risk of CVM and of CVH over 30 months were analyzed using a stratified log-rank test. Results: At baseline about 25% of study participants had sTTR levels below normal in both treatment groups. At Day 28, less than 2% of participants had sTTR levels <20 mg/dL in the acoramidis arm compared with 26% in the placebo arm ( Table 1 ). When acoramidis and placebo treatment groups were pooled based on sTTR levels <20 or ≥20 mg/dL at Day 28, participants with sTTR ≥20 mg/dL were associated with a lower risk of the composite endpoint of CVM or first CVH at Month 30 in comparison with <20 mg/dL ( p <0.0001) ( Figure 1A ). Comparable findings were observed for the individual components (CVM, first CVH) ( Figure 1B and C ). Conclusion: Across treatment groups, sTTR levels above normal range (≥20 mg/dL) at Day 28 were associated with a lower risk of cardiovascular outcomes at Month 30, when compared with sTTR levels below normal range (<20 mg/dL). Thus, these observations demonstrate that higher sTTR levels over time may have the potential for clinical benefits in both CVM and CVH.

Abstract Background and Aims Accurate differentiation of cardiac amyloidosis (CA) from phenotypic mimics remains challenging using current clinical and echocardiographic techniques. The accuracy of a novel artificial intelligence (AI) screening algorithm for echocardiography-based CA detection was assessed. Methods Utilizing a multisite, multiethnic dataset (n = 2612, 52% CA), a convolutional neural network was trained to differentiate CA from phenotypic controls using transthoracic apical four-chamber video clips. External validation was conducted globally across 18 sites including 597 CA cases and 2122 controls. Classification accuracy was assessed on the entire external validation dataset, and subgroup analyses were performed both on technetium pyrophosphate scintigraphy referrals, and individuals matched for age, sex, and wall thickness. Model accuracy was also compared with the transthyretin CA score and the increased wall thickness score within a subset of older heart failure with preserved ejection fraction patients with increased wall thickness. Results Cardiac amyloidosis patients and controls displayed similar age, sex, race, and comorbidities. After the removal of uncertain AI predictions (13%), model discrimination and classification were excellent for the entire external validation dataset [area under the receiver operating characteristic curve (AUROC) 0.93, sensitivity 85%, specificity 93%], irrespective of CA subtype (sensitivity: light-chain = 84%, wild-type transthyretin = 85%, and hereditary transthyretin = 86%). Performance was maintained in subgroup analysis in patients clinically referred for technetium pyrophosphate scintigraphy imaging (AUROC 0.86, sensitivity 77%, specificity 86%) and matched patients (AUROC 0.92, sensitivity 84%, specificity 91%). The AI model (AUROC 0.93) also outperformed transthyretin CA score (AUROC 0.73) and increased wall thickness (AUROC 0.80) scores. Conclusions This AI screening model—using only an apical four-chamber view—effectively differentiated CA from other causes of increased left ventricular wall thickness.

Abstract Background Thromboembolic stroke risk remains a clinical challenge in cardiac amyloidosis (CA) patients with atrial fibrillation because of the increased prevalence of left atrial appendage thrombi irrespective of CHA2DS2-VASc score and a higher prevalence of factors that increase the risk of bleeding with anticoagulation. Left atrial appendage closure (LAAC) is an effective option in patients with atrial fibrillation and high bleeding risk; however, data describing a LAAC strategy for stroke prevention in patients with CA is limited. Among non-CA patients, procedural success and serious complication rates are around 98% and 3% respectively. Purpose In this multicenter retrospective study, we aimed to investigate whether left atrial appendage closure (LAAC) could reduce the risk of bleeding complications and ischemic cerebrovascular events in patients with CA. Methods In an international multi-center retrospective study, patients with CA that underwent LAAC were included. The diagnosis of CA was established on the basis of histologic confirmation or advanced multimodality cardiac imaging as per current consensus statements. Results A total of 28 patients (93% male; 87% ATTR-CA; 13% AL-CA; mean age 80 years) met inclusion criteria. At baseline, mean CHA2DS2-VASc and HAS-BLED scores were 4 and 3 respectively, mean left ventricular ejection fraction was 50%, and mean indexed left atrial volume was 58 mL/m2. 21% of patients had a prior history of ischemic stroke, 14% prior history of hemorrhagic stroke, 7% prior transient ischemic attack, and 54% had a prior history of major or minor bleeding. Procedural success was achieved in 26 patients (93%) with procedural complications occurring in 2 patients (vascular access site bleeding and cardiac tamponade). Regarding in-hospital and follow-up complications, 0% ischemic stroke, 0% hemorrhagic stroke, and major or minor bleeding in 4% of patients. During follow up, device thrombosis occurred in only 1 patient. Conclusion LAAC is a feasible and effective alternative to anticoagulation in patients with CA and excessive bleeding risk, with procedural success and complication rates similar to reported studies of non-CA patients.

Background: ATTR-CM is believed to have a relatively indolent course, with a median survival of ~5 years from heart failure symptoms; however, no data exist as to the rate of progression after disease diagnosis. ATTR-CM is associated with genetic variants, including V122I (present in ~ 3.5% of African Americans), or wild-type TTR (senile systemic amyloidosis - SSA). While there is no effective treatment other than heart transplantation, therapies designed to slow or halt amyloid deposition are in development. The purpose of this study was to characterize the natural history of ATTR-CM to support future therapeutic trials. Methods: Patients with ATTR-CM due to V122I (n = 11) and SSA (n = 18), were enrolled 10.4 ± 11.9 months after diagnosis (range: 0 – 60 months) and assessed every 6 months for up to two years by echocardiography and cardiac magnetic resonance imaging (CMR), with functional capacity assessed by 6-minute walk, and biochemical profile including cardiac troponins and NT-pro-B-type natriuretic peptide (BNP). Baseline data from the full cohort (n = 29), and available data from those completing the 12 month assessment (n = 15) are presented for this on-going study. Results : At baseline, both groups were similar in terms of gender, duration of disease from diagnosis, NYHA, troponin/NT-BNP, and echo or CMR-measured LV wall thickness. SSA patients were older (mean age 76 vs. 71y, P = 0.03), Caucasian (100% vs 0%, P < 0.001), with a history of atrial fibrillation (83% vs. 27%, p = 0.003). During a mean follow-up of 442 days (30–768), there have been 7 deaths (4 V122I; 3 SSA) and 1 cardiac transplantation (SSA), and 10 of 29 (34.5%) were hospitalized at least once (90% for cardiac reasons). For those subjects with a 12 month assessment, LV ejection fraction declined by echo (2.8 %) and CMR (12 %), with minimal changes in wall thickness. Increases were seen in NT-Pro-BNP (87%) and troponin (I: 186%; T: 70%). Worsening of NYHA class occurred in 43% of patients; 6-minute walk distance decreased by 19.2%. Conclusions : Despite reports of a relatively indolent course of ATTR-CM, preliminary data from this ongoing study are the first to demonstrate that quantifiable noninvasive parameters worsen over a 1 year follow up period and are associated with adverse clinical outcomes.

Background: The extent of cardiac involvement has a major impact on clinical outcomes in patients with newly diagnosed light chain (AL) amyloidosis. Here, we present the hematologic responses, major organ deterioration progression-free survival (MOD-PFS) and event-free survival (MOD-EFS), and organ responses by cardiac stage in patients with newly diagnosed AL amyloidosis treated with cyclophosphamide, bortezomib, and dexamethasone (VCd) with or without daratumumab subcutaneous (DARA SC) in the ANDROMEDA trial (NCT03201965). Methods: Key eligibility criteria included newly diagnosed AL amyloidosis with measurable hematologic disease, ≥1 involved organ, cardiac stage I-IIIA (based on the European Modification of the Mayo staging system), eGFR ≥20 mL/min, and absence of symptomatic multiple myeloma. Patients were randomized (1:1) to receive DARA-VCd or VCd alone. All patients received bortezomib (1.3 mg/m2 SC weekly), cyclophosphamide (300 mg/m2 oral [PO] or intravenous [IV] weekly [500 mg maximum]), and dexamethasone (20-40 mg PO or IV weekly) for six 28-day cycles. DARA SC (1800 mg, co-formulated with recombinant human hyaluronidase PH20 in 15 mL) was administered by injection weekly in Cycles 1-2, every 2 weeks in Cycles 3-6, and every 4 weeks thereafter for up to 24 cycles. Disease evaluations occurred every 4 weeks (Cycles 1-6) and every 8 weeks (after Cycle 7) until major organ deterioration, hematologic progression, death, end of study, or withdrawal. The primary endpoint was overall (ie, at any time) hematologic complete response (CR) rate. Secondary endpoints included MOD-PFS, MOD-EFS, organ response rate, time to hematologic response, survival, and safety. Analyses of hematologic CR and MOD-PFS were performed on the intent-to-treat analysis set; cardiac response analyses were based on patients who were evaluable for cardiac response, defined as patients with baseline NT-ProNBP value ≥650 ng/L or baseline NYHA class 3 or 4 and received at least 1 administration of study treatment. Patients without a baseline assessment or post-baseline assessment were censored at randomization for the MOD-PFS analysis. Descriptive statistics were used to summarize overall CR rate and organ response rate. Hazard ratios and corresponding 95% confidence intervals were estimated based on Cox proportional hazard model. Results: A total of 388 patients were randomized to receive DARA-VCd (n=195) or VCd alone (n=193). Baseline characteristics were well balanced between treatment groups. The median age was 64 years and the proportions of patients with cardiac stage I, II, and III were 23%, 40%, and 37%, respectively. The median duration of treatment was 9.6 months for DARA-VCd and 5.3 months for VCd. Median follow-up was 11.4 months (range, 0.03-21.3+). Baseline characteristics were generally balanced across cardiac stages, except increasing cardiac stage was associated with older age (≥65 years), worse Eastern Cooperative Oncology Group performance status, more advanced renal failure (CrCl ≤30), and functionally worse heart failure (NYHA IIIA). Hematologic CR rates were higher in the DARA-VCd group than in the VCd group in patients with cardiac stages I, II, and III at baseline (Table). Cardiac and renal response rates at 6 months were also higher in the DARA-VCd group regardless of cardiac stage at baseline (Table). The hazard ratios (HRs) for MOD-PFS were 0.33, 0.55 and 0.66 for cardiac stages I, II and III, respectively, favoring DARA-VCd. Corresponding HRs for MOD-EFS were 0.24, 0.39, and 0.48, respectively. Rates of any grade adverse events (AEs) were similar in patients with and without cardiac involvement at baseline. Across both treatment arms, rates of serious treatment-emergent AEs were higher in patients with cardiac involvement at baseline than in those without. Conclusions: The benefit of DARA-VCd was retained over VCd alone across cardiac stages for hematologic CR, MOD-PFS, MOD-EFS, and organ responses. Disclosures Minnema: Kite, a Gilead Company: Speakers Bureau; Celgene: Other: travel support, Research Funding; Amgen: Consultancy; Servier: Consultancy. Dispenzieri:Alnylam: Research Funding; Intellia: Research Funding; Janssen: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Celgene: Research Funding. Comenzo:Unum: Consultancy; Prothena: Consultancy, Research Funding; Amgen: Consultancy; Sanofi: Consultancy; Caleum: Consultancy; Janssen: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Kastritis:Janssen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Wechalekar:Takeda: Honoraria, Other: Travel; Celgene: Honoraria; Janssen: Honoraria, Other: Advisory; Caelum: Other: Advisory. Witteles:Pfizer: Membership on an entity's Board of Directors or advisory committees; Alnylam Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Maurer:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Alnylam: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ionis: Research Funding; Eidos: Research Funding; Akcea: Research Funding. Tran:Janssen: Current Employment, Current equity holder in publicly-traded company. Qin:Janssen: Current Employment. Vasey:Janssen Research & Development: Current Employment, Current equity holder in publicly-traded company. Tromp:Janssen: Current Employment, Current equity holder in publicly-traded company. Weiss:Janssen: Current Employment, Current equity holder in publicly-traded company. Vermeulen:Janssen: Current Employment, Current equity holder in publicly-traded company. Jaccard:Janssen: Consultancy, Honoraria, Other: A.J. has served in a consulting or advisory role for Janssen and has received honoraria from, received research funding from, and had travel, accommodations, or other expenses paid for or reimbursed by Janssen., Research Funding; Celgene: Honoraria, Other: A.J. has served in a consulting or advisory role for Janssen and has received honoraria from, received research funding from, and had travel, accommodations, or other expenses paid for or reimbursed by Celgene., Research Funding.

Cardiomyopathy is a manifestation of transthyretin amyloidosis (ATTR), which is an underrecognized systemic disease whereby the transthyretin protein misfolds to form fibrils that deposit in various tissues and organs. ATTR amyloidosis is debilitating and associated with poor life expectancy, especially in those with cardiac dysfunction, but a variety of treatment options have recently become available. Considered a rare disease, ATTR amyloidosis may be more prevalent than thought, particularly in older persons. Diagnosis is often delayed because of a lack of disease awareness and the heterogeneity of symptoms at presentation. Given the recent availability of effective treatments, early recognition and diagnosis are especially critical because treatment is likely more effective earlier in the disease course. The Amyloidosis Research Consortium recently convened a group of experts in ATTR amyloidosis who, through an iterative process, agreed on best practices for suspicion, diagnosis, and characterization of disease. This review describes these consensus recommendations for ATTR associated with cardiomyopathy as a resource to aid cardiologists and others in the recognition and diagnosis of ATTR associated with cardiomyopathy. Included in this review is an overview of red flag signs and symptoms and a recommended diagnostic approach, including testing for monoclonal protein, scintigraphy, or biopsy and, if ATTR associated with cardiomyopathy is identified, TTR genotyping.