Transthyretin Amyloid Cardiomyopathy Research Articles

Comparative assessment of extracellular volume metrics in predicting adverse outcomes in patients with transthyretin amyloid cardiomyopathy

Abstract Introduction The indexed total extracellular volume of the myocardium (iECV) has recently been proposed to be superior in predicting adverse outcome in severe aortic stenosis as compared to conventional extracellular volume (ECV). So far, no study has assessed the comparative predictive performance of both measures in transthyretin amyloid cardiomyopathy (ATTR-CM). Aim We aimed to assess and compare the predictive performance of conventional ECV against iECV in determining adverse outcomes in patients with ATTR-CM. Methods From 2012 to 2023, patients with ATTR-CM undergoing contrast cardiac magnetic resonance (CMR) imaging prior to any specific treatment were enrolled. Both, conventional ECV and iECV were quantified on CMR alongside left ventricular volumetrics and late gadolinium enhancement. Adverse outcome was defined as a composite endpoint of hospitalization for heart failure and/or death. Results Analysis of 178 patients with ATTR-CM (82% males, mean age 77±8 years) revealed a mean conventional ECV of 47±13% and a mean iECV of 46±21 mL/m2, with a median follow-up of 2.5 years (IQR: 1.00-4.08 years). Conventional ECV was significantly associated with the composite endpoint (HR=1.03, 95%CI=1.01–1.05, p=0.006), outperforming iECV (HR=1.01, 95%CI=1.00–1.02, p=0.010). On multivariate analysis, adjusted for age, sex and left ventricular function, conventional ECV remained associated with the composite endpoint (p=0.002), while iECV demonstrated a slightly less significant association (p=0.003). Kaplan-Meier analysis, stratified by conventional ECV tertiles, revealed that patients in the highest tertile (ECV ≥53%) demonstrated the highest event rate (p = 0.043 by log rank test, see Figure 1A), in contrast to iECV (p=NS, Figure 1B). Conclusions High conventional ECV, among CMR fibrosis markers, is linked to heart failure hospitalizations and death in ATTR-CM, demonstrating superior prognostic value compared to iECV. Conventional ECV measurements may offer enhanced risk stratification for patients with ATTR-CM.

Prognostic impact of SGLT2-inhibitor therapy on survival in patients with transthyretin amyloid cardiomyopathy

Abstract Background Sodium-glucose co-transporter 2 inhibitors (SGLT2i) significantly improve cardiovascular outcomes in patients with heart failure across the whole spectrum of ejection fraction. Recently published data indicates the safety and tolerability of SGLT2i therapy in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). However, there is a lack of evidence regarding the impact of SGLT2i therapy on clinical outcomes in those patients. Purpose This study aims to investigate the association between SGLT2i therapy and clinical outcomes in patients with ATTR-CM. Methods This is an analysis of a prospective registry conducted at an expert center for hypertrophic cardiomyopathies. We included all participants with a confirmed diagnosis of ATTR-CM, who were enrolled until December 2022. Prior and concomitant SGLT2i treatment was systemically assessed according to the patient interview and medical records. Patients’ outcomes were retrieved from local medical and health insurance records. Results We enrolled 116 patients, of whom 7 patients (6%) were treated with SGLT2i at inclusion and 44 patients (38%) were started on SGLT2i therapy during the observational period while 65 patients (56%) were SGLT2i-naïve. There were no significant differences in baseline characteristics between groups, as shown in the table. Median (interquartile range) age was 80 (76-82) years with 15% females. Median N-terminal pro-brain natriuretic peptide (NT-proBNP) was 2844 (1519-5033) pg/ml, median estimated glomerular filtration rate (eGFR) 58 (46-69) ml/min/1,73m2, and median troponin T 56 (34-83) pg/ml. During a median follow-up of 2.6 (1.8-3.7) years, 28 patients (24%) died, of whom 6 patients (5%) were in the treatment group and 22 patients (19%) in the control group. In univariate Cox-regression analysis, SGLT2i treatment was significantly associated with a lower mortality (HR 0.325, 95%CI 0.132-0.802, p=0.015). This association persisted after adjusting for age and sex (HR 0.347, 95%CI 0.139-0.867, p=0.023). However, when treatment initiation time was considered, the benefit did not remain statistically significant. No significant associations between SGLT2i treatment and worsening heart failure hospitalizations or cardiovascular death were observed. Conclusion In a prospective registry-based cohort of patients with ATTR-CM, SGLT2i therapy was associated with significantly better survival, with a potential treatment initiation time bias. These results suggest that SGLT2i may exert beneficial effects in patients with ATTR-CM and warrant a randomized controlled trial.

Long-term all-cause and cardiovascular-related mortality in patients with ATTR-CM treated with continuous tafamidis vs placebo to tafamidis by NAC stage at baseline

Abstract Background The National Amyloidosis Centre (NAC) staging system is used to stratify patients with transthyretin amyloid cardiomyopathy (ATTR-CM) into prognostic categories.[1] Purpose This post hoc analysis evaluated all-cause and cardiovascular (CV)-related mortality in patients receiving tafamidis 80 mg or placebo by NAC stage at baseline in the phase 3 Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) and its long-term extension (LTE) study.[2,3] Methods Patients in ATTR-ACT were randomised to tafamidis meglumine 80 mg, 20 mg, or placebo for 30 months, stratified by transthyretin (TTR) genotype (wild-type or variant) and NYHA class (I or II/III). Patients with an NT-proBNP <600 ng/l or eGFR <25 ml/min/1.73m² were excluded. After completing ATTR-ACT, patients could receive tafamidis 61 mg up to 60 months in the open-label LTE study. Heart transplant and cardiac mechanical assist device implantation were treated as death in the mortality assessments. Secondary analyses were change from baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical and overall summary (CS, OS) scores and frequency of all-cause and CV-related hospitalisations. Results Of 350 patients, 42%, 38% and 20% had NAC stage I, II and III at baseline, respectively. Patients at stage III tended to be older, more likely female, and with a variant TTR genotype vs those at a lower stage (Table). At the end of follow-up, all-cause mortality was consistently lower in patients continuously treated with tafamidis vs those who initially received placebo across NAC stages (I: 36% vs 61%; : 55% vs 74%; III: 69% vs 88%). The hazard ratio (HR [95% CI]) for all-cause mortality with continuous tafamidis treatment vs placebo to tafamidis was 0.43 (0.26-0.70; P<0.001), 0.51 (0.33-0.80; P=0.003) and 0.75 (0.44-1.29; P=0.298), for patients at stage I, II and III, respectively. Similar trends were observed in CV-related mortality at the end of follow-up, where HR (95% CI) for continuous tafamidis-treated patients at stage I, II and III was 0.39 (0.22-0.70; P=0.001), 0.51 (0.31-0.85; P=0.009) and 0.75 (0.42-1.33; P=0.320). The separation of survival curves was seen in the first few months of tafamidis treatment in patients at NAC stage I (Figure A). Such early separation was not seen in those at stage II or III. Starting from Month 18, statistically smaller declines in KCCQ-OS and CS scores were frequently observed in the continuous tafamidis vs placebo to tafamidis groups at stages I and II. Across NAC stages, all-cause and CV-related hospitalisations were lower in the continuous tafamidis vs placebo to tafamidis group (Figure B). Conclusions Continuous tafamidis treatment reduced mortality and hospitalisations (both all-cause and CV-related) across all NAC stages. These reductions were larger and occurred earlier in patients with NAC stage I, emphasising the importance of early disease-modifying treatment in patients with ATTR-CM.[3] NCT01994889, NCT02791230.

Transthyretin stabiliser therapy in patients with transthyretin amyloid cardiomyopathy: a systematic review and meta-analysis

Abstract Introduction The safety and efficacy of transthyretin (TTR) stabilisers in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) remains unclear. Objectives We aimed to assess whether TTR stabilisers are effective and safe to promote medical optimisation in patients with ATTR-CM. Methods We systematically searched PubMed, Embase and Cochrane for studies comparing the use of TTR stabilisers with placebo or no TTR stabilisers in patients with ATTR-CM. Statistical analyses were performed using RevMan 5.1.7. Heterogeneity was examined with the Cochran Q test and I2 statistics. Risk ratios (RR) and hazard ratios (HR) with 95% confidence intervals (CI) were computed with a random-effects model for binary endpoints. Results We included 2 randomised controlled trials (RCT) and 12 observational studies, comprising 3324 patients, of whom 1563 (47,02%) received TTR stabilisers. Follow-up ranged from 7 to 36 months. TTR stabilisers were significantly associated with lower all-cause mortality (RR 0.32; 95% CI 0.18-0.57; p<0.01) and cardiovascular hospitalisation (RR 0.67; 95% CI 0.52-0.86; p=0.02) as compared with control group. In a sub analysis of RCTs and multivariate-adjusted data, the composite endpoint of all-cause mortality, heart transplant, and cardiac assist device implantation yielded significant lower rates in the TTR stabiliser group (HR 0.46; 95% CI 0.28-0.73; p=0.01). Conclusion In patients with ATTR-CM, TTR stabilisers were associated with significant lower rates of all-cause mortality and cardiovascular hospitalisations as compared with control group.

Artificial intelligence-guided screening of under-recognized cardiomyopathies adapted for point-of-care echocardiography

Abstract Background Point-of-care ultrasonography (POCUS) enables access to cardiac imaging directly at the bedside but is limited by brief acquisition, variation in acquisition quality, and lack of advanced protocols. Purpose To develop and validate deep learning models for detecting underdiagnosed cardiomyopathies on cardiac POCUS, leveraging a novel acquisition quality-adapted modeling strategy. Methods To develop the models, we identified transthoracic echocardiograms (TTEs) of patients across five hospitals in a large U.S. health system with transthyretin amyloid cardiomyopathy (ATTR-CM, confirmed by Tc99m-pyrophosphate imaging), hypertrophic cardiomyopathy (HCM, confirmed by cardiac magnetic resonance), and random controls from the same period enriched for the presence of severe AS. In a sample of 290,245 TTE videos, we used novel augmentation approaches and a customized loss function to weigh image and view quality to train a multi-label, view agnostic video-based convolutional neural network (CNN) to discriminate the presence of ATTR-CM, HCM, and/or AS+ and AS- controls. Models were tested across 3,758 real-world POCUS videos from 1,879 studies in 1,330 independent emergency department (ED) patients from 2011 through 2023 (A). Results Our multi-label, view-agnostic classifier demonstrated state-of-the-art performance in discriminating ATTR-CM (AUROC 0.98 [95%CI: 0.96-0.99]) and HCM (AUROC 0.95 [95% CI: 0.94-0.96]) on standard TTE studies. Automated metrics of anatomical view correctness confirmed significantly lower quality in POCUS vs TTE videos (median view classifier confidence of 0.63 [IQR: 0.44-0.88] vs 0.93 [IQR: 0.69-1.00], p<0.001). When deployed to POCUS videos, our algorithm effectively discriminated ATTR-CM and HCM with AUROC of up to 0.94 (parasternal long-axis (PLAX)), and 0.85 (apical 4 chamber (A4C)) (B), corresponding to positive diagnostic odds ratios of 46.7, and 25.5, respectively. In total, 18/35 (51.4%) of ATTR-CM and 32/57 (41.1%) of HCM patients in the POCUS cohort had a positive AI screen in the year before their eventual confirmatory imaging (C). Conclusions We define and validate an AI framework that enables scalable, opportunistic screening of under-diagnosed cardiomyopathies using POCUS.

Serial changes of 99mTc- pyrophosphate uptake in patients with hereditary transthyretin amyloid cardiomyopathy treated with tafamidis

Abstract Objective Transthyretin amyloid cardiomyopathy (ATTR-CM) arises from the deposition of amyloid in the heart, resulting in adverse outcomes. Tafamidis has demonstrated potential in slowing disease progression. Our research group, alongside others, has documented cases where decrease in cardiac tracer uptake were observed through bone scintigraphy after tafamidis treatment.[1-8] This study aims to assess the efficacy of Technetium-99m (99mTc)-pyrophosphate (PYP) scintigraphy in longitudinally monitoring tafamidis treatment for hereditary ATTR-CM over an extended follow-up period. Methods We retrospectively analyzed a prospective cohort of hereditary ATTR-CM patients treated with tafamidis (61 mg/day) retrospectively. A control group comprised hereditary ATTR-CM patients who hadn't received eplontersen, inotersen, tafamidis, or patisiran. 99mTc-PYP SPECT/CT scans were conducted at baseline and 1-3 years post-treatment, measuring visual score, planar heart to contralateral lung (H/CL) ratio, and volumetric heart to lung (H/L) ratio. Results Twenty hATTR-CM patients received tafamidis, with the other ten in the control group. After a 2-year follow-up, the tafamidis group experienced a significant decrease in volumetric heart to lung (H/L) ratio (3.817 to 3.011, p < 0.001), while the control group showed no significant change (3.775 to 3.621, p = 0.121)(Figure 1B). Significant decreases in volumetric H/L ratio were noted in the first year of tafamidis treatment (-21.71%), with minimal changes in the subsequent two years (-0.77% in the second year and -2.41% in the third year)(Figure 2B). Conclusion A significant initial reduction in 99mTc-PYP uptake was observed in hereditary ATTR-CM patients during the first year of tafamidis treatment. However, this effect was not sustained in the subsequent two years. Further investigation is warranted to comprehend the long-term efficacy of tafamidis in these patients.Changes in 99mTc-PYP uptake at 2 yearsChanges between 1st, 2nd and 3rd year

Study design of the CARDIO-TTRansform cardiac magnetic resonance imaging substudy

Abstract Background Cardiac magnetic resonance (CMR) with extracellular volume (ECV) mapping can track treatment response in patients with cardiac amyloidosis by assessing changes in cardiac amyloid burden along with associated changes in structure and function. The CARDIO-TTRansform trial is a phase 3, multicentre, double-blind, randomised, placebo-controlled trial designed to assess the efficacy and safety of eplontersen in transthyretin amyloid cardiomyopathy (ATTR-CM). Eplontersen is a ligand-conjugated antisense oligonucleotide designed to reduce hepatic production of transthyretin protein, the amyloid fibril precursor protein in ATTR-CM. Patients with hereditary or wild-type ATTR-CM on available standard of care were randomized 1:1 to receive 45 mg of eplontersen or placebo via subcutaneous injection every 4 weeks. Patients in the main study with no contraindication to CMR were invited to participate in this sub-study. Purpose The primary objective is to measure the change in amyloid burden (defined as % change in ECV from baseline) over time in patients receiving eplontersen versus placebo. Methods Participants will undergo CMR with ECV mapping at baseline, 25, 49, 97 and 140 weeks (Figure 1). Images will be acquired under a standardized protocol comprising cine imaging with steady state free precession sequence, late gadolinium enhancement imaging (LGE) and T1 mapping. T1 mapping will be performed before the administration of contrast and will be repeated 15 minutes post-contrast using the same slice locations, to produce ECV maps. Results In the main study, 1432 patients were randomized from 120 sites across 20 countries. Of these patients, 157 patients were enrolled in the CMR sub-study, from 6 centers across 4 countries. Images will be read centrally at the end of the study. All participants in the study will also receive serial transthoracic echocardiography with strain analysis to correlate findings with conventional imaging techniques, and a subset of patients from the CMR substudy will be co-enrolled in a scintigraphy substudy for further characterization of amyloid deposition in their heart. Conclusion The CARDIO-TTRansform CMR substudy represents the largest CMR study of ATTR-CM. The CMR sub-study has enrolled a broad global population of patients with hereditary and wild-type ATTR-CM and will provide key information on the impact of eplontersen on the cardiac amyloid load and the associated change in structure and function.

Changes in the diagnostic landscape of transthyretin amyloid cardiomyopathy (ATTR-CM): a comparison of tests ordered and test Intervals in 2020 Q4 and 2023 Q4

Abstract Background Transthyretin Amyloid Cardiomyopathy (ATTR-CM) is a genetic disease caused when misfolded transthyretin protein is deposited in the myocardium. Amyloidosis driven stiffness in heart muscles results in heart failure symptoms. ATTR-CM is underdiagnosed, requiring specialized tests to identify the condition. Purpose This paper examines and compares diagnostic tests and the time intervals between rounds of testing conducted to identify ATTR-CM in 2020 Q4 and 2023 Q4 in France (FR), Germany (DE), Italy (IT), Spain (ES) and the United Kingdom (UK). Methods A multi-centre online medical chart review was performed between November and December 2020, with 210 (FR: 46, DE: 40, IT: 43, ES: 42, UK: 39) cardiologists/internists providing data on 320 (FR: 71, DE: 63, IT: 64, ES: 63, UK: 59) patients diagnosed with ATTR-CM; and between October and November 2023, with 225 (FR: 45, DE: 48, IT: 48, ES: 45, UK: 39) cardiologists/Internists providing data on 780 (FR: 151, DE: 163, IT: 172, ES: 175, UK: 119) patients. Participants were screened for ATTR-CM patient management. We analysed the diagnostic tests ordered and tracked the intervals between batteries of tests to understand how the timing of diagnosis has changed across the EU4+UK. Results The average number of ATTR-CM diagnostic tests received by reported patients rose from 5.9 in 2020 to 7.4 in 2023, with ECHO with strain imaging (87%), Genetic tests (78%), Cardiac MRI (74%), Laboratory tests (67%), and Scintigraphy tests (65%) as the top 5 tests in Q4 2023. There was a notable increase in the use of ECHO with strain imaging, Laboratory tests, and Scintigraphy tests recorded in the Spanish patient cohort (p<0.01). Reported patients in Italy, Spain & UK received an increased average number of tests (p<0.05) [Table 1]. The recorded interval between the 1st and 2nd test batteries remained consistent between Q4 2020 and Q4 2023 (4.8-4.9 wks.), but the interval between the 2nd to 3rd rounds increased from 4.3 to 5.0 weeks. Timings between batteries increased in the France, Germany, Italy and UK data. Reported patients in Germany continue to experience the shortest intervals between batteries of tests (4.1 wks. between 1st and 2nd; 4.4 wks. between 2nd and 3rd batteries). Between Q4 2020 and Q4 2023, reported patients in Spain had an increase in the average number of tests received from 5.2 to 7.2, and were the only group with decreased time intervals (7.3 to 4.5 wks. between 1st and 2nd; 5.8 to 5.1 wks. between 2nd and 3rd batteries) Conclusion Results indicate that the use of certain diagnostic tests as well as the number of tests used to diagnose ATTR-CM has increased, however, intervals between testing batteries have also increased. This suggests that the increase in the number of tests used to diagnose ATTR-CM is possibly negating the necessity for more frequent testing. Further research in needed to confirm this and assess its impact on early detection of ATTR-CM.Table 1:Diagnostic Procedures by RegionTable 2:Testing battery intervals

Disease-modifying treatments in transthyretin amyloid cardiomyopathy: a meta-analysis of randomized controlled trials

Abstract Background and Aims Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive and life-threatening disease. With advancements in pharmacology, numerous novel medications are currently under investigation. However, the effects of these treatments on long-term outcomes remain elusive and inconclusive. Methods PubMed, MEDLINE, Embase, and the Cochrane Library were searched for literature inclusion until January 2024. Only phase 3, high-quality, randomized controlled trials related to ATTR-CM were considered for enrolment. Endpoints included all-cause mortality, six-minute walk distance, Kansas City Cardiomyopathy Questionnaire–Overall Summary Score, and serum N-terminal pro-B-type natriuretic peptide (NTproBNP) levels. A random-effects model was applied for meta-analysis. Results Three landmark trials (ATTR-ACT, APOLLO-B, ATTRibute-CM) comprising 866 patients with ATTR-CM were pooled. 66.6% of the subjects were administered with medical treatment. Consistent improvements in all-cause mortality (P=0.001), 6-minute walk distance (P=0.045), Kansas City Cardiomyopathy Questionnaire–Overall Summary Score (P<0.001), and serum NTproBNP level (P=0.002) were present by medical treatment. At 12 months, only NT-proBNP showed significant improvement in the pooled analysis of the APOLLO-B and ATTRibute-CM results. At 30 months, the pooled analysis of ATTR-ACT and ATTRibute-CM demonstrated significantly better all-cause mortality and KCCQ scores in patients received mediation. Conclusions Disease-modifying Treatments is associated with better survival, functional capacity, quality of life, and NTproBNP level in patients with ATTR-CM. Extended follow-up duration might be needed to demonstrate efficacies.

Tafamidis for the treatment of transthyretin cardiac amyloidosis (ATTR-CM) - Real-world data from a tertiary center

Abstract Introduction Tafamidis 61mg was shown to be the first treatment to reduce cardiovascular hospitalizations and to improve survival in patients with Transthyretin Amyloid Cardiomyopathy (ATTR-CM). Real-world data on the efficacy of transthyretin (TTR) stabilizers in patients with Heart Failure (HF) due to ATTR-CM is scarce. Purpose We aimed to assess the use of tafamidis in our center, that features a dedicated Cardiomyopathy Clinic. Methods We conducted an all-comers single-centre prospective study of consecutive patients with symptomatic HF due to ATTR-CM followed up to November 2023. As per site protocol, the diagnosis was established according to the ESC algorithm and all patients were assessed at least twice yearly. Disease management plans include HF treatment tailored to ATTR-CM (CHAD-STOP) and treatment with disease-modifying tafamidis 61mg. The latter is considered in patients who meet the local protocol criteria, including key inclusion criteria - NYHA class I-II - and none of the exclusion criteria - e.g. estimated glomerular filtration rate (GFR) <25mL/min. The primary endpoint was time to cardiovascular hospitalization or all-cause death. Results A total 226 ATTR-CM patients were identified, of whom 181 had a follow-up of at least 6 months and were included in the analysis (mean age 84 ± 7 years; 81% males, 16% hATTR-CM). Overall, there were 84 patients treated with tafamidis. Compared to non-treated patients, those receiving tafamidis were younger (mean age 83 vs. 86 years, p=0.007), more often with a lower NYHA functional class (e.g., NYHA I-II: 92 vs. 62%; p<0.001), scored higher on performance scales (e.g., Karnovsky >70: 67 vs 33%; p<0.001), and had less comorbidities (e.g., GFR: 40 vs. 30mL/min; p<0.001). Over a median follow-up of 16 months, 68 (37.6%) patients met the primary endpoint (49.5% vs. 22.6%, respectively; p<0.001). In multivariate analysis, treatment with tafamidis was an independent predictor of the primary endpoint (HR 0.24; 95%CI 0.13-0.43; p<0.001), adjusted for NYHA functional class (HR for NYHA I-II vs. III-IV: 0.54; 95%CI 0.32-0.92; p=0.023), NT-proBNP (HR 1.83; 95%CI 1.09-3.08; p=0.023) and high-sensitivity Troponin T (HR per 10 units: 1.01; 95%CI 1.01-1.02; p=0.024). These findings were consistent in multivariate analysis with any combination of the prior variables with either creatinine, GFR, albumin, or TTR type (wild-type vs. mutated). These results were primarily driven due to association of tafamidis treatment with increased survival. Conclusion The use of tafamidis in a cohort of patients with symptomatic HF and ATTR-CM was shown to be independently associated with reduced cardiovascular hospitalization or all-cause death. The effect had a similar magnitude of effect to that of the ATTR-ACT trial, suggesting that our local protocol based on the key criteria from this trial may allow for appropriate patient selection.

Tafamidis treatment for transthyretin amyloid cardiomyopathy: results from an open-label, early-access, long-term study extension in an all-comers population

Abstract Background In the pivotal Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT NCT01994889), tafamidis significantly reduced mortality and cardiovascular hospitalization in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). Given the high clinical unmet need and the favorable benefit-to-risk profile of tafamidis, there was a justification to provide patients with an option for early access to treatment as part of the ATTR-ACT long-term extension study (LTE; NCT02791230). Purpose To assess long-term safety in an all-comers population receiving early access to tafamidis. Methods Following protocol amendment (20 July 2018), patients with ATTR-CM, not previously enrolled in ATTR-ACT, and without commercial access to tafamidis, were enrolled in the LTE early-access study arm in 13 countries. Patients received open-label, once-daily tafamidis free acid 61 mg for up to 60 months, until they gained product access by prescription or study discontinuation by the sponsor. All-cause and cardiovascular (CV)-related mortality, CV-related hospitalization, and treatment-emergent adverse events (TEAEs) were assessed. Results Of 1481 patients enrolled in the early-access cohort, 1476 received at least one dose of tafamidis and were included in the analysis. Mean (SD) age at enrollment was 76.5 (7.8) years old, 37.5% were ≥80 years old, and 88.8% were male. Most patients (85.6%) had wild-type ATTR-CM, and 14.9%, 52.9%, 30.8%, and 1.3% were in New York Heart Association (NYHA) Class I, II, III, and IV, respectively. Over a mean (SD) follow-up period of 17.7 (13.8) months, all-cause and CV-related mortality rates were 23.4% and 13.8%, respectively (Table). Mean frequency of CV-related hospitalization per year was 0.28 (0.60). Serious TEAEs and TEAEs leading to discontinuation of the study were observed in 0.6% of patients (both); no new safety signals were identified. Conclusions Findings from the early-access cohort of the ATTR-ACT LTE highlight the safety of tafamidis treatment in an all-comers ATTR-CM patient population.

Increase in serum TTR levels observed with acoramidis treatment in patients with transthyretin amyloid cardiomyopathy (ATTR-CM): insights from ATTRibute-CM and its open-label extension

Abstract Background/Introduction Patients with ATTR-CM can have lower circulating TTR levels, which is associated with worsening of cardiac function and increased risk of cardiovascular mortality.[1] Acoramidis has been shown to reduce cardiovascular mortality and hospitalization, while increasing circulating TTR levels, in the ATTRibute-CM phase 3 study.[2] Purpose I. Evaluate serum TTR levels in participants (pts) receiving acoramidis vs those who received tafamidis in the placebo group in ATTRibute-CM at Month 30. II. Evaluate serum TTR levels in pts who transitioned from placebo+tafamidis to acoramidis in the open-label long term extension (OLE) study. Methods ATTRibute-CM study: Eligible pts with ATTR-CM were randomized in a 2:1 ratio to receive acoramidis or placebo for 30 months. Pts in both groups had the option of initiating open-label, commercially available tafamidis after 12 months in the study. Upon completion of Month 30, pts were invited to participate in the OLE study. In OLE, pts who had previously received acoramidis continued acoramidis, and those who had previously received placebo+tafamidis were switched to acoramidis-only treatment. All pts in the OLE study received acoramidis only. Change in serum TTR levels in ATTRibute-CM and OLE at data cutoff (Oct 9, 2023) are summarised using descriptive statistics. Results In the phase 3 study, efficacy analyses were performed in 611 pts, of which 61 of 409 (14.9%) and 46 of 202 (22.8%) received tafamidis in acoramidis and placebo groups, respectively. The median time until tafamidis initiation was 17.8 and 16.1 months, respectively; median exposure duration was 11.6 and 10.5 months, for acoramidis and placebo groups, respectively.[3] Change from baseline (CFB) in serum TTR levels remained unchanged at Month 30 in the placebo-only group (mean [SD] = –0.4 [4.92] mg/dL). Characteristics of pts analysed are described in Fig. 1. A total of 380/611 pts (62.2%) entered the OLE study (229 pts continued acoramidis only, and 23 switched from placebo+tafamidis to acoramidis). At the time of data cutoff, 214 pts who had received acoramidis only completed Month 6 in OLE versus 18 who switched from placebo+tafamidis to acoramidis. At Month 30 in ATTRibute-CM, CFB in serum TTR levels were higher for patients who received acoramidis only than those receiving placebo+tafamidis (Fig 2A). Serum TTR levels increased further in pts who switched from placebo+tafamidis to acoramidis in OLE (Fig. 2B). The OLE study is ongoing, and this analysis includes pts who completed the Month 6 visit at time of data-cut. Conclusion(s) CFB in serum TTR levels were higher in pts receiving acoramidis only than those receiving placebo+tafamidis at Month 30 in the double-blind study. A further significant increase in serum TTR levels was observed in those who received placebo+tafamidis and switched to acoramidis in OLE.

RV-PA uncoupling is a strong predictor of 3-year all-cause mortality in transthyretin amyloid cardiomyopathy

Abstract Background Right ventricle to pulmonary artery coupling (RV-PAc) describes the right ventricle's ability to adjust to an increased afterload which, in case of transthyretin amyloid cardiomyopathy (ATTR-CM), can result from increased left ventricular diastolic stiffness due to fibril deposition. While RV-PAc is a validated prognostic parameter in pulmonary arterial hypertension (PAH), its prognostic relevance in ATTR-CM remains unclear. This study sought to evaluate the prognostic implications of impaired RV-PAc on survival in ATTR-CM. Methods In this two-centre study, RV-PAc was investigated by the echocardiographic surrogate of ratio of tricuspid annular plane systolic excursion to estimated pulmonary arterial systolic pressure (TAPSE/PASP) in 418 ATTR-CM patients, all treated with TTR stabilizer. The primary outcome was all-cause mortality. Receiver operation curves and Youden’s J analysis were applied to identify an optimal cut-off value of RV-PAc ratio. Results Within a median time of 631 (IQR 361-983) days after diagnosis, 14.4% of patients died. RV-PAc ratio at first presentation emerged as a robust marker for risk stratification with a determined optimal cut-off of 0.382mm/mmHg (area under the curve (AUC) 0.746, 95% CI 0.68-0.82). Patients with RV-PAc ratio ≤0.382mm/mmHg (impaired RV-PAc, n=158) exhibited significantly lower survival (HR 4.07, 95% CI 2.26-7.33, p<0.001) within 3 years of follow up than those with RV-PAc ratio > 0.382mm/mmHg. In multivariate Cox regression analysis, incorporating a range of known prognostic variables, reduced RV-PAc was a strong echocardiographic predictor of mortality (Hazard Ratio (HR) 2.99, 95% Confidence Interval (CI) 1.63-5.51, p <0.001). Conclusion Impaired adaption of the RV to increased afterload is associated with worse outcome in ATTR-CM patients. RV-PAc ratio can serve as an echocardiographic predictor for all-cause mortality within three years after diagnosis. Therefore, determination of RV-PAc could improve risk stratification for ATTR-CM patients.Figure_1_Kaplan-Meier curves

Validation of two simple scores to identify increased risk of transthyretin amyloid cardiomyopathy in heart failure with preserved ejection fraction

Abstract Background Transthyretin Amyloid Cardiomyopathy (ATTR-CM) is an emerging underdiagnosed cause of heart failure (HF). 99mTc-3, 3-diphosphono-1,2-propanodicarboxylic acid (DPD) allows ATTR-CM diagnosis in the absence of histology. Recently two simple clinical scores to identify increased risk of ATTR-CM in patients with heart failure and preserved left ventricular ejection fraction have been developed and validated. Purpose To assess the prevalence of ATTR-CM in a Mediterranean cohort of patients at risk, and to externally validate the Mayo ATTR-CM and T-Amylo scores. We also explore its diagnostic accuracy improvement by adding N-terminal pro-B-type natriuretic peptide (NT-proBNP). Methods Retrospective cohort study of consecutive patients with suspected cardiac amyloidosis referred to DPD between March 2017 and November 2020. Scans were reported using a visual grading system (0 to 3 increasingly; 2-3 positive) on planar images. Patients with clonal dyscrasia or those without rule-out tests (serum free light chain assay, and serum and urine protein electrophoresis with immunofixation) were excluded. Discrimination was obtained using the area under the curve (AUC) of the receiver operating characteristic (ROC) curve based on the ATTR-CM score [High risk: score ≥ 6. Components: age (60-69 = 2 points; 70-79 = 3 points; ≥80 = 4 points), male sex = 2 points, hypertension = -1 point, ejection fraction <60% = 1 point, posterior wall thickness ≥12 mm = 1 point, relative wall thickness (septal + posterior wall thickness/left ventricular end diastolic diameter) >0.57 = 2 points], and T-amylo score [High risk: score > 6. Components: age ≥ 80 years = 1 point, interventricular septum thickness ≥16 mm = 2 points, low QRS interval voltage = 2 points, male gender = 3 points, and carpal tunnel syndrome = 3 points. Calibration was assessed with the Hosmer-Lemeshow goodness-of-fit test. Results A total of 200 patients were included with a mean age of 78.5 ± 11 years, 45.5% male, left ventricular ejection fraction 58% ± 12 and a median NT-proBNP of 2310 pg/mL (Table 1). 81 (40.5%) and 10 (5.0%) patients were categorized as a high-risk group due to ATTR-CM score value ≥6 and simplified T-Amylo score >6, respectively. Prevalence of ATTR-CM was 17.5%. The AUC for the Mayo ATTR-CM and T-Amylo scores in our cohort were 0.83 (95% CI 0.75-0.90) and 0.79 (95% CI 0.69-0.88) respectively, with an appropriated calibration (Figure 1). The addition of NT-proBNP to the scores did not increase the AUC (p=0.19 and p=0.08), with a Net Reclassification Improvement (NRI) of 0.055 (95% CI - 0.110 to 0.206) and 0.033 (95% CI - 0.113 to 0.224) respectively. Conclusion These two simple clinical scores are valid and reliable tools for ATTR-CM diagnosis in our Mediterranean cohort. Added to clinical suspicion, can improve the diagnostic workup for ATTR-CM, irrespective of NT-proBNP values.

Clinical and laboratorial profile of patients with ATTR cardiomyopathy: comparison between wild type and p.Val142Ile forms in the Brazilian population

Abstract Background In Brazil, besides the wild type (wt) form, transthyretin amyloid cardiomyopathy (ATTR-CM) is predominantly caused by hereditary form with Val142Ile mutation. Considering that both forms occur in elderly people, the clinical presentation may be similar. We sought to compare the clinical presentation of patients with wt and Val142Ile mutation in a Brazilian cohort of ATTR-CM patients. Methods Among the 642 patients enrolled in REACT/SP, 283 presented ATTR-CM, being 85 wt and 90 Val142Ile patients. We compared the main clinical characteristics between groups. Results The wt in comparison to Val142Ile patients, respectively, presented: older age (78.4+/-8.5 vs 74.2+/-8.1 y.o., p = 0.0009); similar proportion of males (82% vs 81%, p=0.85); lower proportion of blacks (11% vs 39%, p=0.0001); similar prevalence of heart failure (HF) symptoms (85% vs 79%, p=0.33); higher prevalence of syncope (13% vs 2%, p=0.008) and Pacemakers (PM) implantation (8% vs 1%, p=0.027); similar prevalence of neuropathy manifestations (38% vs 51%, p=0.17); lower creatinine (1.5+/-0.8 vs 2.1+/-2.1 mg/dL, p=0.02) and NT-ProBNP levels (2860.0+/-2843.3 vs. 5488.3+/-5455.6 pg/ml, p=0.0001); reduced interventricular septal thickness (15.6+/-3.3 vs 17.0+/-3.3 mm, p= 0.006), posterior left ventricular (LV) posterior wall thickness (14.2+/-2.4 vs 16.2+/-4.4 mm, p=0.0003), higher LV ejection fraction (52.0+/-10.1 vs 48.2+/-13.6%, p=0.038), higher global LV longitudinal strain (8.6+/-8.7 vs 3.4+/-9.8, p=0.0003), smaller LV diastolic diameter (45.9+/-6.1 vs 43.0+/-7.3 mm, p=0.005) at 2D-Echocardiogram. Conclusions In the Brazilian population wt and Val142Ile patients had similar clinical presentation regarding HF and neuropathy symptoms, but higher prevalence of syncope and PM in wt patients. Conversely, Val142Ile patients presented more severe amyloid cardiac infiltration.

Differential echocardiographic profiles in immunoglobulin light chain and transthyretin amyloid cardiomyopathy: insights from speckle tracking analysis

Abstract Background Amyloid cardiomyopathy is mainly caused by two main subtypes of amyloidosis; immunoglobulin light chains cardiomyopathy (AL-CM) and transthyretin cardiomyopathy (TTR-CM). Purposes The aim of the present study was to elucidate the differences in echocardiographic findings between AL-CM and TTR-CM using speckle tracking echocardiography. Methods The study included patients with a confirmed diagnosis of cardiac amyloidosis through cardiac biopsy and who underwent transthoracic echocardiography between March 2013 and October 2022. The relative apical sparing index (RASI) was calculated using speckle tracking echocardiography: mean apical strain value/(mean basal strain value + mean mid strain value). Results The final study population consisted of 50 patients with a confirmed diagnosis of cardiac amyloidosis diagnosed pathologically (AL-CM: 21 patients, TTR-CM: 29 patients). Mean age was 72 ± 11 years, 70% being male. AL-CM exhibited a lower left ventricular mass index compared to TTR-CM (124.5 ± 48.9 vs. 152.2 ± 39.2 g/m2, P = 0.001). In 35 patients available with longitudinal strain analysis, no significant difference was observed in left ventricular global longitudinal strain between the two subgroups (-9.9 ± 4.8 vs. -9.3 ± 2.4% , P = 0.63). However, RASI was significantly lower in AL-CM compared to TTR-CM as shown in Figure (0.92 ± 0.29 vs. 1.46 ± 0.53, P = 0.001). Receiver operating characteristic curve analysis shows a RASI cut-off value of <1.0 proved useful in differentiating the diagnosis of AL-CM from TTR-CM (sensitivity: 81%, specificity: 70%, AUC:0.82), and RASI <1.0 remained a significant association with the diagnosis of AL-CM, even after adjusted by conventional echocardiographic variables. Conclusion Apical sparing phenomenon was more remarkable in TTR-CM compared with AL-CM, although global longitudinal strain was comparable between the two groups. RASI was useful for the discrimination of cardiac amyloidosis subtypes.

Effect of tafamidis on left atrial function in patients with transthyretin amyloid cardiomyopathy

Abstract Background Transthyretin amyloid cardiomyopathy (ATTR-CM) is characterized by the functional and structural consequences of amyloid infiltration predominantly within the ventricles, causing biventricular wall thickening. Amyloid infiltration can be observed in left atrium in ATTR-CM, however, the association of left atrial (LA) myocardial function with cardiovascular events and changes in LA myocardial function with tafamidis administration have not been elucidated. Purpose The aim of this study was to identify the association between baseline LA reservoir function evaluated by left atrial reservoir strain and cardiovascular events. Furthermore, monitoring the LA reservoir function before and after tafamidis administration, we also investigated the baseline factors associated with changes in LA reservoir function in patients with ATTR-CM. Methods We studied 55 patients with biopsy-proven ATTR-CM who were started on tafamidis in our institution between July 2019 and December 2022 (age: 76 ± 2 years, male: 93%). The primary endpoint was defined as hospitalization for heart failure or cardiovascular death during a median follow-up period of 28 ± 4 months after tafamidis administration. Furthermore, we assessed the factors associated with changes in LA function before and 25 ± 3 months after tafamidis administration for 49 patients who underwent sufficient follow-up echocardiography. Results During the follow-up period, 8 patients had cardiovascular death or cardiovascular hospitalization. The Kaplan-Meier curve indicated that the occurrence of cardiovascular events for patients with LA strain ≥ the median 8.6% was significantly lower than for those with LA strain < 8.6% (log-rank P =0.002; Figure A). Furthermore, comparing LA strain before and after tafamidis administration, the group with worsening LA strain tended to be older (79.0 ± 2.0 years vs. 73.6 ± 3.3 years, P=0.004), have higher brain natriuretic peptide (350 ± 83 pg/mL vs. 199 ± 47 pg/mL, P=0.003), have lower global longitudinal strain (GLS) (9.8 ± 1.4 % vs. 12.6 ± 1.6 pg/mL, P=0.008), and higher relative apical longitudinal strain index (1.63 ± 0.4 % vs. 1.14 ± 0.2 %, P=0.021). The multivariate logistic regression analysis was that age, GLS and relative apical longitudinal strain index were the independent determinants for deterioration of LA strain after tafamidis administration (Figure B). Conclusion In our study, baseline LA reservoir function was found to be closely associated with cardiovascular events after tafamidis administration, while age, GLS and relative apical longitudinal strain index were associated with worsening LA strain after tafamidis administration. Our findings could represent an additional parameter for the effective management of patients with ATTR-CM.Figure AFigure B

Delays in diagnosis and treatment initiation of ATTR cardiac amyloidosis: a real-world data analysis

Abstract Introduction Cardiac amyloidosis (CA) is a serious condition characterized by the accumulation of abnormal protein deposits in the heart muscle, leading to functional impairments and, ultimately, heart failure. Transthyretin amyloid cardiomyopathy (ATTR-CM) is the most common form encountered in CA diagnosis with previously underestimated prevalence. ATTR-CM poses a diagnostic challenge, with a substantial number of cases diagnosed late and at advanced stages. The availability of specific pharmacological treatment using the transthyretin-stabilizer tafamidis further emphasizes the need for timely diagnosis. Here, we aim to assess delays in diagnosis and initiation of therapy in a real-world collective of patients with ATTR-CM. Methods All individuals diagnosed from 01/2018 to 05/2023 with ATTR-CM at our university hospital, Germany, were systematically assessed for eligibility in this study. Specifically, we enrolled patients who were undergoing transthyretin stabilizer therapy. The investigation aimed to determine the duration, in days, from the initial suspicion of heart disease to the definitive diagnosis of ATTR-CM. It was also investigated whether the diagnosis of ATTR-CM was made more quickly over time as awareness increased. Additionally, the study assessed the time elapsed until patients received pharmacological therapy following the confirmed diagnosis. The study was approved by the local ethics committee (23-11500-BO). Results After screening of 194 consecutive patients, 154 were included in the analysis, while 40 patients were excluded due to insufficient records. The results of this study reveal that a median of 300 (113-962) days elapsed from the initial suspicion of amyloidosis to the final confirmation. Initial indications of CA often presented as nonspecific symptoms such as unclear dyspnea (16.2% n=25), abnormal echocardiography (75.3% n=116), or, in rare cases, incidental findings (8.4% n=13). Following the diagnosis, an additional median of 84 (46-163.5) days passed before the first prescription of a transthyretin stabilizer. To assess an improvement of ATTR-CM diagnosis over time, we stratified the data into tertiles by date of first diagnosis. The results showed a gradually decrease in medium time to diagnosis of 466 (181-1035) days in the earliest tertile (2018-2019) to 389 (141-1508) days in the most recent tertile (2022-2023) (p<0.001). Conclusion This study shows a major healthcare deficit and underscores the medical need for improved screening procedures and diagnostic modalities to expedite the timely diagnosis of CA, as early identification of the condition is crucial for enhancing the quality of life for patients and preventing life-threatening complications.

Guideline-Directed Medical Therapy Intolerance in Heart Failure.

This Teachable Moment discusses guideline-directed medical therapy intolerance in a woman in her 80s with heart failure with reduced ejection fraction and transthyretin amyloid cardiomyopathy.

Prevalence of transthyretin amyloid cardiomyopathy in patients hospitalised for heart failure with preserved ejection fraction in an LATAM center

Abstract Introduction Transthyretin Amyloid cardiomyopathy (ATTR-CM) usually presents as heart failure with preserved ejection fraction (HFpEF). Its diagnosis has a significant clinical impact, as specific treatment is currently available. Purpose To assess the prevalence of ATTR-CM in patients hospitalised for HFpEF and increased septal thickness in our institution of general community hospital in Latin America (LATAM). Methods Cross-sectional study. Patients hospitalised for HFpEF (>50%) and septal thickness ≥ 12 mm during the period from 8/2019 to 1/2023 were prospectively included. Patients with pacemaker, significant left valve disease and end-stage renal failure (creatinine clearance < 30 ml/min/BSA) were excluded. A pyrophosphate bone scintigraphy (PYP) was planned to be performed in order to assess ATTR-CM. The prevalence of ATTR-CM and its 95% confidence interval were calculated. Results A PYP was performed in 59/82 patients hospitalised for HFpEF. Median age was 85 [IQR 78-88] years, and 54% were women. At admission, 61% (n=36) had atrial fibrillation and the median NT Pro-Bnp was 3536 [1700-7748] pg/mL. The mean left ventricle ejection fraction was 57% (+/- 5%). The prevalence of ATTR-CM diagnosed by PYP was 19% (95% CI 9.7-30.1, n=11). There were no significant clinical differences between patients who performed a PYP and did not. Patients with ATTR-CM had lower blood pressure and higher septal thickness, NT Pro-Bnp and troponin levels compared to patients without ATTR-CM (TABLE). Conclusion In patients admitted for HFpEF and increased septal thickness, the diagnosis of ATTR-CM was relatively common (one of five had ATTR-CM) in our region (LATAM). We believe that systemic assessment with PYP should be performed in patients hospitalised with HFpEF and increased wall thickness.