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Hereditary transthyretin amyloidosis (ATTRv) is associated with polyneuropathy, cardiomyopathy, or both. The effects of eplontersen on cardiac structure and function were assessed. NEURO-TTRansform was an open-label trial involving 144 adults with ATTRv polyneuropathy (49 patients [34%] with cardiomyopathy) receiving eplontersen throughout and compared with a historical placebo group (n = 60; 30 patients [50%] with cardiomyopathy) from the NEURO-TTR trial at week 65. Treatment effect (eplontersen vs placebo), presented as mean difference (95% confidence interval) was analyzed after adjusting for age, sex, region, baseline value, ATTRv disease stage, previous ATTRv treatment, and V30M transthyretin variant. There were notable differences at baseline between the eplontersen group and historical placebo. In the cardiomyopathy subgroup, 65 weeks of eplontersen treatment was associated with improvement from baseline relative to placebo in left ventricular ejection fraction of 4.3% (95% confidence interval 1.40–21.01; P =.049) and stroke volume 10.64 mL (95% confidence interval 3.99–17.29; P =.002) while the remainder of echocardiographic parameters remained stable. Eplontersen was associated with stable or improved measures of cardiac structure and function vs historical placebo in patients with ATTRv polyneuropathy and cardiomyopathy. Further investigation into eplontersen's effect on transthyretin amyloid cardiomyopathy is being conducted in the CARDIO-TTRansform trial. vATTR, variant transthyretin; LV, left ventricle; E/e′, ratio of early diastolic mitral inflow velocity to early diastolic mitral annulus velocity; NT-proBNP, N-terminal prohormone of brain natriuretic peptide. [Display omitted] [ABSTRACT FROM AUTHOR]

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Cardiac amyloidosis is increasingly recognized as an underlying cause of left ventricular wall thickening, heart failure, and arrhythmia with variable clinical presentation. Due to the subtle cardiac findings in early transthyretin cardiac amyloidosis and the availability of therapies that can modify but not reverse the disease progression, early recognition is vital. In light chain amyloidosis, timely diagnosis and treatment can significantly improve survival. In this manuscript, we review the clinical, imaging, and electrocardiographic clues that should raise suspicion for cardiac amyloidosis and provide a simplified diagnostic workup algorithm that ensures an accurate diagnosis. The evolution of the noninvasive diagnosis of cardiac amyloidosis has significantly influenced our understanding of disease prevalence, presentations, and outcomes. However, clinical recognition of clues and red flags remains the most important factor in advancing the care of patients with cardiac amyloidosis. [ABSTRACT FROM AUTHOR]

Introduction: Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive, fatal and under-recognized disease. This targeted literature review assessed the extent and consequences of diagnostic delay and misdiagnosis in ATTR-CM. Methods: The Embase database was searched together with proceedings of eight cardiology conferences to identify publications or abstracts on ATTR-CM. Outcomes of interest were time from symptom onset to diagnosis, rates of delayed diagnosis and misdiagnosis, and costs, healthcare resource use or clinical outcomes whilst undiagnosed/misdiagnosed. Results: Twenty-three articles were included. Weighted means of reported mean and median diagnostic delays were 6.1 and 3.4 years for wild-type (ATTRwt-CM) and 5.7 and 2.6 years for hereditary (ATTRv-CM). Misdiagnosis occurred in 34–57% of patients when reported. Evaluation and misdiagnosis by multiple healthcare providers before receiving an ATTR-CM diagnosis was common, and there was evidence that patients undergo unnecessary or inappropriate evaluations or treatments while misdiagnosed. Diagnostic "red flags" were reported to be underused. Data on the consequences of delay for patients and health systems were sparse, but given the progressive nature of ATTR-CM, delay is likely to have adverse consequences. Conclusion: ATTR-CM patients commonly experience diagnostic delay and misdiagnosis. Efforts are required to provide timely diagnosis so that patients can benefit from earlier access to new disease-modifying therapies. [ABSTRACT FROM AUTHOR]

Aims: Advances in diagnostic imaging have increased the recognition of coexisting transthyretin cardiac amyloidosis (ATTR‐CA) and severe aortic stenosis (AS), with a reported prevalence between 8–16%. In this prospective study, we aimed to evaluate the implications of ATTR‐CA on outcomes after transcatheter aortic valve replacement (TAVR). Methods and results: At two academic centres, we screened patients with severe AS undergoing TAVR for ATTR‐CA. Using Kaplan–Meier analysis, we compared survival free from death and a combined endpoint of death and first heart failure hospitalization between patients with and without ATTR‐CA. Cox proportional‐hazards models were used to determine the association of ATTR‐CA with these endpoints. The rate of heart failure hospitalization was compared amongst those with and without ATTR‐CA. Overall, 204 patients (83 years, 65% male, Society of Thoracic Surgeons score 6.6%, 72% New York Heart Association class III/IV) were included, 27 (13%) with ATTR‐CA. Over a median follow‐up of 2.04 years, there was no difference in mortality (log rank, P = 0.99) or the combined endpoint (log rank, P = 0.79) between patients with and without ATTR‐CA. In Cox proportional‐hazards models, the presence of ATTR‐CA was not associated with death. However, patients with ATTR‐CA had increased rates of heart failure hospitalization at 1 year (0.372 vs. 0.114 events/person‐year, P < 0.004) and 3 years (0.199 vs. 0.111 events/person‐year, P = 0.087) following TAVR. Conclusion: In moderate‐risk patients with severe AS undergoing TAVR, there was a 13% prevalence of ATTR‐CA, which did not affect mortality. The observed increase in heart failure hospitalization following TAVR in those with ATTR‐CA suggests the consequences of the underlying infiltrative myopathy. [ABSTRACT FROM AUTHOR]

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Transthyretin cardiomyopathy (ATTR-CM) was an exclusion criterion in randomized clinical trials of sodium-glucose cotransporter 2 inhibitors (SGLT2i). This study sought to assess the effectiveness and tolerability of SGLT2i in patients with ATTR-CM. Data of 2,356 consecutive ATTR-CM patients (2014-2022) were analyzed: 260 (11%) received SGLT2i. After comparing the groups according to the treatment, 14 variables were significantly different—age and N-terminal pro–B-type natriuretic peptide were included in the model. A propensity score reflecting the likelihood of being treated with SGLT2i for each patient was determined using 16 variables. The study comprised 220 patients treated with SGLT2i (age 77 ± 2 years; 82.3% wild-type ATTR-CM; left ventricular ejection fraction 45.8% ± 11%) and 220 propensity-matched control individuals. Adequacy of matching was verified (standardized differences: <0.10 between groups). Discontinuation rate for SGLT2i was 4.5%; at 12 months, SGLT2i treatment was associated with less worsening of NYHA functional class, N-terminal pro–B-type natriuretic peptide, estimated glomerular filtration rate, and fewer new initiations of loop diuretic agent therapy. Over 28 months (Q1-Q3: 18-45 months), SGLT2i therapy was associated with lower all-cause mortality (HR: 0.57; 95% CI: 0.37-0.89; P = 0.010), cardiovascular mortality (HR: 0.41; 95% CI: 0.24-0.71; P < 0.001), heart failure (HF) hospitalization (HR: 0.57; 95% CI: 0.36-0.91; P = 0.014), and the composite outcome of cardiovascular mortality and HF hospitalization (HR: 0.57; 95% CI: 0.38-0.84; P = 0.003). SGLT2i treatment in ATTR-CM patients was well tolerated and associated with favorable effects on HF symptoms, renal function, and diuretic agent requirement over time. SGLT2i treatment was associated with reduced risk of HF hospitalization and cardiovascular and all-cause mortality, regardless of the ejection fraction, despite the effect size being likely overestimated. In the absence of randomized trials, these data may inform clinicians regarding the use of SGLT2i in patients with ATTR-CM. [Display omitted] [ABSTRACT FROM AUTHOR]

This document, published in the journal Circulation, discusses the development of a novel biomarker for transthyretin amyloidosis (ATTR), a disease characterized by the deposition of amyloid fibrils composed of misfolded transthyretin (TTR). The researchers developed a probe called transthyretin aggregate detector 1 (TAD1) to detect ATTR fibrils and aggregates in patient tissues and blood. They validated the probe's ability to bind to ATTR fibrils and found that it displayed high sensitivity and specificity. The researchers also tested TAD1 on plasma samples from patients with ATTR and found that it could detect a unique biomarker that decreased in response to treatment. The study suggests that TAD1 may be a useful tool for early detection and monitoring of ATTR. However, the study has limitations, including a limited sample size and the need for independent validation. The work was supported by various funding sources, and the authors disclose potential conflicts of interest. [Extracted from the article]

Transthyretin amyloid cardiomyopathy (ATTR-CM), particularly wild type (wtATTR-CM), is thought to mainly affect men. Non-invasive diagnosis and approved therapeutics have been associated with increased disease recognition. We investigated the trajectory of ATTR-CM diagnosis in women. This observational study utilized data collected on 140 consecutive ATTR-CM patients diagnosed between 2005 and 2022 who are followed at the Oregon Health and Science University Amyloidosis Clinic. Subgroup analysis was performed on patients with wtATTR-CM which included 113 subjects (80.1%). The proportion of women among patients diagnosed with ATTR-CM prior to 2019 was compared with that of those diagnosed 2019–2022 (2019 was the year of tafamidis approval by the FDA). The clinical characteristics of male and female ATTR-CM patients were compared as well. Of the 140 ATTR-CM patients, 16 (11.4%) were women (age 77 ± 9 years) and 124 (88.6%) were men (age 76 ± 9 years). There was an increase in the rate of women diagnosed with ATTR-CM from pre 2019 to 2019–2022 in the overall cohort (4/68 [5.9%] vs 12/72 [16.7%]) and wild type subgroup (0/51 [0%] vs 7/62 [11.3%]). There were several differences in baseline clinical characteristics between women and men in this cohort, yet all women had a clear clinical phenotype of ATTR-CM. There has been a significant increase in the rate of wtATTR-CM diagnoses in women, who presented with clear phenotypes of ATTR-CM. Further studies are needed to understand the effect of increased recognition of ATTR-CM in women on disease epidemiology, natural history, and outcomes. • The phenotypic presentation of ATTR-CM is similar in women and men in this single center study • Increased rate of diagnosis of ATTR-CM in women is driven by an increase in diagnosis of the wild type form. • This increased diagnosis of wtATTR-CM in women is temporally related to the non-invasive diagnosis and tafamidis. [ABSTRACT FROM AUTHOR]

Transthyretin cardiac amyloidosis (ATTR-CM) may associate with sudden cardiac death. We report on the mode of death and outcomes with implantable cardioverter defibrillators (ICDs) in a cohort with ATTR-CM. A single center observational cohort study of patients with ATTR-CM diagnosed between 2005 and 2019. ICD implant was at discretion of treating cardiologists. Medians are expressed with 25th,75th percentiles. Eighty-four patients with ATTR-CM (age 73.5 ± 9.7 years, 94% male, median follow-up 21.1 months (11.4–38.1). Nineteen patients (23%) underwent ICD implantation – 18 for primary and 1 for secondary prevention. In the primary prevention ICD group, 1 patient had 2 inappropriate shocks, 1 patient had appropriate ATP on 3 occasions. One patient (mixed ischemic cardiomyopathy and ATTR-CM) with secondary prevention ICD had 15 appropriate shocks in 3 episodes of VT storm. In patients without ICD, ambulatory monitoring review (14,764 h) did not reveal sustained ventricular arrhythmia. Excluding the one patient with secondary prevention ICD, 5 (28%) in the primary prevention ICD group and 22 (34%) in the non-ICD group died, p = 0.14. Mode of death did not vary between both groups. Patients with ATTR-CM and primary prevention ICD infrequently receive appropriate device therapy without differing in mode of death, which was mainly related to progressive heart failure, compared to those without ICD. • Appropriate device therapy is uncommon with primary prevention ICD in ATTR-CM. • Sustained ventricular arrhythmia was not detected with ambulatory monitoring of patients without ICD. • ICD was not associated with lower mortality as compared with the group without ICD. • Mode of death was similar with versus without ICD and was largely due to progressive heart failure. [ABSTRACT FROM AUTHOR]

Keywords: amyloidosis; atrial fibrillation; atrial flutter; hypertrophy, left ventricular EN amyloidosis atrial fibrillation atrial flutter hypertrophy, left ventricular 1730 1732 3 11/29/22 20221129 NES 221129 Atrial fibrillation (AF) and atrial flutter (AFL) are common in patients with transthyretin cardiac amyloidosis (ATTR-CM) and can present years before diagnosis of ATTR-CM.[1] Prior data from our amyloidosis center, which serves both urban and rural parts of the Pacific Northwest, demonstrated an AF/AFL prevalence of 73% among patients with wild type or hereditary ATTR-CM2 - a treatable cause of heart failure if recognized in a timely fashion.[3] Technetium-99m pyrophosphate scintigraphy (Tc-99m PYP) is a simple, noninvasive diagnostic option[3] that allows for screening of ATTR-CM in broader populations, however, there is paucity of data regarding screening for ATTR-CM in patients with AF/AFL. Footnotes 1 Nonstandard Abbreviations and Acronyms AF atrial fibrillation AFL atrial flutter ATTR-CM transthyretin cardiac amyloidosis LV left ventricular LVH left ventricular hypertrophy Tc-99m PYP technetium-99m pyrophosphate scintigraphy 2 For Sources of Funding and Disclosures, see page 1732. Graph In the present study, where systematic screening for ATTR-CM in patients with LVH and AF/AFL was instituted, routine screening of more than 1600 AF/AFL patients resulted in 65 patients undergoing Tc-99m PYP - of which only 1 patient was diagnosed with ATTR-CM. [Extracted from the article]