BACKGROUND: Diagnostic and therapeutic advances have led to much greater awareness of transthyretin cardiac amyloidosis (ATTR-CA). We aimed to characterize changes in the clinical phenotype of patients diagnosed with ATTR-CA over the past 20 years. METHODS: This is a retrospective observational cohort study of all patients referred to the National Amyloidosis Centre (2002–2021) in whom ATTR-CA was a differential diagnosis. RESULTS: We identified 2995 patients referred with suspected ATTR-CA, of whom 1967 had a diagnosis of ATTR-CA confirmed. Analysis by 5-year periods revealed an incremental increase in referrals, with higher proportions of patients having been referred after bone scintigraphy and cardiac magnetic resonance imaging (2% versus 34% versus 51% versus 55%, chi-square P <0.001). This was accompanied by a greater number of ATTR-CA diagnoses, predominantly of the wild-type nonhereditary form, which is now the most commonly diagnosed form of ATTR-CA (0% versus 54% versus 67% versus 66%, chi-square P <0.001). Over time, the median duration of associated symptoms before diagnosis fell from 36 months between 2002 and 2006 to 12 months between 2017 and 2021 (Mann–Whitney P <0.001), and a greater proportion of patients had early-stage disease at diagnosis across the 5-year periods (National Amyloidosis Centre stage 1: 34% versus 42% versus 44% versus 53%, chi-square P <0.001). This was associated with more favorable echocardiographic parameters of structure and function, including lesser interventricular septal thickness (18.0±3.8 mm versus 17.2±2.6 mm versus 16.9±2.3 mm versus 16.6±2.4 mm, P =0.01) and higher left ventricular ejection fraction (46.0%±8.9% versus 46.8%±11.0% versus 47.8%±11.0% versus 49.5%±11.1%, P <0.001). Mortality decreased progressively during the study period (2007–2011 versus 2012–2016: hazard ratio, 1.57 [95% CI, 1.31–1.89], P <0.001; and 2012–2016 versus 2017–2021: hazard ratio, 1.89 [95% CI, 1.55–2.30], P <0.001). The proportion of patients enrolled into clinical trials and prescribed disease-modifying therapy increased over the 20-year period, but even when censoring at the trial or medication start date, year of diagnosis remained a significant predictor of mortality (2012–2016 versus 2017–2021: hazard ratio, 1.05 [95% CI, 1.03–1.07], P <0.001). CONCLUSIONS: There has been a substantial increase in ATTR-CA diagnoses, with more patients being referred after local advanced cardiac imaging. Patients are now more often diagnosed at an earlier stage of the disease, with substantially lower mortality. These changes may have important implications for initiation and outcome of therapy and urgently need to be factored into clinical trial design.

Aims Transthyretin amyloid cardiomyopathy (ATTR‐CM) is often assumed to be associated with wild‐type TTR genotype (ATTRwt) in elderly patients (aged ≥70), some of whom are not offered genetic testing. We sought to estimate the prevalence, clinical characteristics and prognostic implications of transthyretin (TTR) variants among elderly patients diagnosed with ATTR‐CM. Methods and results Data from consecutive patients over 70 years of age diagnosed with ATTR‐CM at the UK National Amyloidosis Centre between January 2010 and August 2022 were retrospectively evaluated. All patients underwent clinical evaluation, biochemical tests, echocardiography and TTR genotyping. The study outcome was all‐cause mortality. The study population consisted of 2029 patients with ATTR‐CM (median age 79 years at diagnosis, 13.5% females, 80.4% Caucasian). Variant ATTR‐CM (ATTRv‐CM) was diagnosed in 20.7% (n = 421) of the study population of whom 327 (77.7%) carried V122I, 47 (11.2%) T60A, 16 (3.8%) V30M and 31 (7.3%) other pathogenic TTR variants. During a median (range) follow‐up of 29 (12–48) months, ATTRv‐CM was associated with increased all‐cause mortality compared to ATTRwt‐CM, with the poorest survival observed in V122I‐associated ATTRv‐CM (p < 0.001). Univariable and multivariable logistic regression analyses in those with ATTR‐CM showed younger age at diagnosis (odds ratio [OR] 0.85 per year, p < 0.001), female sex (OR 2.73, p < 0.001), Afro‐Caribbean ethnicity (OR 65.5, p < 0.001), atrial fibrillation (OR 0.65, p = 0.015), ischaemic heart disease (OR 0.54, p = 0.007), peripheral polyneuropathy (OR 5.70, p < 0.001) and orthostatic hypotension (OR 6.29, p < 0.001) to be independently associated with ATTRv‐CM. Conclusion Up to 20.7% of elderly patients with ATTR‐CM have a pathogenic TTR variant. These findings support routine sequencing of the TTR gene in all patients with ATTR‐CM regardless of age.

Aims To perform evaluation of widely embraced bone scintigraphy-based non-biopsy diagnostic criteria (NBDC) for ATTR amyloid cardiomyopathy (ATTR-CM) in clinical practice, and to refine serum free light chain (sFLC) ratio cut-offs that reliably exclude monoclonal gammopathy (MG) in chronic kidney disease. Methods and results A multi-national retrospective study of 3354 patients with suspected or histologically proven cardiac amyloidosis (CA) referred to specialist centres from 2015 to 2021; evaluations included radionuclide bone scintigraphy, serum and urine immunofixation, sFLC assay, eGFR measurement and echocardiography. Seventy-nine percent (1636/2080) of patients with Perugini grade 2 or 3 radionuclide scans fulfilled NBDC for ATTR-CM through absence of a serum or urine monoclonal protein on immunofixation together with a sFLC ratio falling within revised cut-offs incorporating eGFR; 403 of these patients had amyloid on biopsy, all of which were ATTR type, and their survival was comparable to non-biopsied ATTR-CM patients (p = 0.10). Grade 0 radionuclide scans were present in 1091 patients, of whom 284 (26%) had CA, confirmed as AL type (AL-CA) in 276 (97%) and as ATTR-CM in only one case with an extremely rare TTR variant. Among 183 patients with grade 1 radionuclide scans, 122 had MG of whom 106 (87%) had AL-CA; 60/61 (98%) without MG had ATTR-CM. Conclusion The NBDC for ATTR-CM are highly specific [97% (95% CI 0.91-0.99)] in clinical setting, and diagnostic performance was further refined here using new cut-offs for sFLC ratio in patients with CKD. A grade 0 radionuclide scan all but excludes ATTR-CM but occurs in most patients with AL-CA. Grade 1 scans in patients with CA and no MG are strongly suggestive of early ATTR-type, but require urgent histologic corroboration.

Introduction Transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly recognised cause of heart failure. 3–4% of individuals of African descent carry a transthyretin gene mutation encoding the p.V142I variant, a powerful risk factor for development of variant ATTR-CM. This equates to 1.6 million potential carriers in the USA alone. We report findings from a multi-parametric, multi-modality phenotyping study of p.V142I ATTR-CM. Hypothesis The phenotype of p.V142I variant ATTR-CM is an aggressive form of ATTR CM. Methods A retrospective phenotyping study of 395 patients with p.V142I-ATTR-CM at our national referral centre was conducted. Patients underwent evaluation at the centre at time of diagnosis, including clinical and functional assessment, echocardiography, biomarker analysis; a subgroup had cardiac magnetic resonance imaging. 395 wild type ATTR-CM patients matched for independent predictors of prognosis (NAC Disease Stage, age, decade of first presentation) were used as a comparator group. Results Average age of pV142I ATTR-CM patients was 75.8 years. There was significant functional impairment (38.2% of cases NHYA ≥ III, mean 6 minute walk test distance 272m). Significant impairment of echocardiographic parameters was seen; mean LVEF 43%, global longitudinal strain −9.1%, TAPSE 14.2mm, E/E prime 17.4, E/A ratio 2.47 with high frequency of at least moderate mitral (44%) and tricuspid regurgitation (51%). Median NT-proBNP was 3165 ng/L (IQR 4224). Arrhythmias were common with 17.4% of patients having a bradyarrhythmia, 26.1% having atrial fibrillation/flutter, and 5.6% having a pacemaker at presentation. Uni and multivariate cox regression analysis identified serum troponin, tricuspid regurgitation, LVEF, TAPSE and lower systolic blood pressure as independent predictors of prognosis. Prognostic parameters were statistically significantly worse and five year survival by Kaplan Meier analysis was significantly reduced when compared to matched WT ATTR-CM patients (p&lt;0.05) (Figure 1). Mean serum high sensitivity troponin T and extracellular volume (ECV) by cardiac magnetic resonance (CMR) was higher in p.V142I ATTR-CM than WT ATTR-CM cases (94 ng/L vs 74.2 ng/L, p&lt;0.05, 58% vs 55%, p&lt;0.05). Interventricular wall thickness however was lower in p.V142I ATTR-CM than matched WT cases (17.2 mm vs 16.8 mm). Conclusion p.V142I ATTR-CM is an aggressive phenotype, with significant functional impairment, burden of regurgitant valvular disease and systolic impairment resulting in poor survival. Patients with p.V142I ATTR-CM had a higher burden of amyloid infiltration as measured as shown by ECV measurements on CMR, higher serum troponin and lower wall thickness when compared to a matched cohort of WT ATTR-CM patients. This novel observation suggests a unique disease mechanism that is more cardiotoxic which results in myocyte loss and myocardial thinning as opposed to myocyte hypertrophy. Funding Acknowledgement Type of funding sources: None.

AimsTransthyretin cardiac amyloidosis (ATTR-CM) is a progressive and fatal cardiomyopathy. Treatment options in patients with advanced ATTR-CM are limited to cardiac transplantation (CT). Despite case series demonstrating comparable outcomes with CT between patients with ATTR-CM and non-amyloid cardiomyopathies, ATTR-CM is considered to be a contraindication to CT in some centers, partly due to a perceived risk of amyloid recurrence in the allograft. We report long-term outcomes of CT in ATTR-CM at two tertiary centers.Materials and methods and ResultsWe retrospectively evaluated ATTR-CM patients across two tertiary centers who underwent transplantation between 1990 and 2020. Pre-transplantation characteristics were determined and outcomes were compared with a cohort of non-transplanted ATTR-CM patients. Fourteen (12 male, 2 female) patients with ATTR-CM underwent CT including 11 with wild-type ATTR-CM and 3 with variant ATTR-CM (ATTRv). Median age at CT was 62 years and median follow up post-CT was 66 months. One, three, and five-year survival was 100, 92, and 90%, respectively and the longest surviving patient was Censored &gt; 19 years post CT. No patients had recurrence of amyloid in the cardiac allograft. Four patients died, including one with ATTRv-CM from complications of leptomeningeal amyloidosis. Survival among the cohort of patients who underwent CT was significantly prolonged compared to UK patients with ATTR-CM generally (p &lt; 0.001) including those diagnosed under age 65 years (p = 0.008) or with early stage cardiomyopathy (p &lt; 0.001).ConclusionCT is well-tolerated, restores functional capacity and improves prognosis in ATTR-CM. The risk of amyloid recurrence in the cardiac allograft appears to be low.