Transthyretin Amyloid Cardiomyopathy Research Articles

Effect of Tafamidis on Cardiac Function in Patients With Transthyretin Amyloid Cardiomyopathy

Tafamidis has been shown to improve survival in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) compared with placebo. However, its effect on cardiac function has not been fully characterized. To examine the effect of tafamidis on cardiac function in patients with ATTR-CM. This was an exploratory, post hoc analysis of the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT), a multicenter, international, double-blind, placebo-controlled phase 3 randomized clinical trial conducted from December 2013 to February 2018. The ATTR-ACT included 48 sites in 13 counties and enrolled patients aged 18 to 90 years with ATTR-CM. Data were analyzed from July 2018 to September 2023. Patients were randomized to tafamidis meglumine, 80 mg or 20 mg, or placebo for 30 months. Patients were categorized based on left ventricular (LV) ejection fraction at enrollment as having heart failure with preserved ejection fraction (≥50%), mildly reduced ejection fraction (41% to 49%), or reduced ejection fraction (≤40%). Changes from baseline to month 30 in LV ejection fraction, LV stroke volume, LV global longitudinal strain, and the ratio of early mitral inflow velocity to septal and lateral early diastolic mitral annular velocity (E/e') were compared in patients receiving tafamidis, 80 mg, vs placebo. A total of 441 patients were randomized in ATTR-ACT, and 436 patients had available echocardiographic data. Of 436 included patients, 393 (90.1%) were male, and the mean (SD) age was 74 (7) years. A total of 220 (50.5%), 119 (27.3%), and 97 (22.2%) had heart failure with preserved, mildly reduced, and reduced LV ejection fraction, respectively. Over 30 months, there was less pronounced worsening in 4 of the echocardiographic measures in patients receiving tafamidis, 80 mg (n = 176), vs placebo (n = 177) (least squares mean difference: LV stroke volume, 7.02 mL; 95% CI, 2.55-11.49; P = .002; LV global longitudinal strain, -1.02%; 95% CI, -1.73 to -0.31; P = .005; septal E/e', -3.11; 95% CI, -5.50 to -0.72; P = .01; lateral E/e', -2.35; 95% CI, -4.01 to -0.69; P = .006). Compared with placebo, tafamidis, 80 mg, attenuated the decline of LV systolic and diastolic function over 30 months in patients with ATTR-CM. Approximately half of patients had mildly reduced or reduced LV ejection fraction at enrollment, suggesting that ATTR-CM should be considered as a possible diagnosis in patients with heart failure regardless of underlying LV ejection fraction. ClinicalTrials.gov Identifier: NCT01994889.

Predictive utility of health-related quality of life and the 6-minute walking test in transthyretin amyloid cardiomyopathy - a comparison

Abstract Introduction Both health-related quality of life (HR-QoL) as well as submaximal physical performance as assessed using the 6-minute walking test (6-MWT) have been shown to predict outcome in heart failure. However, it is currently unclear how the predictive utility of different HR-QoL measurement tools compares to the 6-MWT in transthyretin amyloid cardiomyopathy (ATTR-CM). Aims To evaluate predictive utility of the Kansas City Cardiomyopathy Questionnaire (KCCQ), the Minnesota Living with Heart Failure Questionnaire (MLHFQ) and the EuroQol Five Dimensions Questionnaire (EQ-5D) in comparison to the 6-MWT in patients with ATTR-CM. Methods and results 186 patients diagnosed with ATTR-CM were included and data from 474 visits (2.55 per patient) was analysed. All scores and distance walked in the 6-MWT were transformed into Z-values by subtracting the mean and dividing by the standard deviation. In a cox regression analysis for all-cause mortality adjusted for age and sex, the KCCQ [Hazard Ratio (HR): 0.560, p = < 0.001], the EQ-5D visual analogue scale (HR: 0.712, p = 0.005) and the MLHFQ (HR: 0.613, p = < 0.001) proved predictive of outcome. For heart failure hospitalisation, the KCCQ (HR: 0.455, p = < 0.001), the EQ-5D overall score (HR: 0.753, p = 0.007), the EQ-5D visual analogue scale (HR: 0.631, p = < 0.001) and the MLHFQ score (HR: 0.466, p = < 0.001) were shown to be of high predictive utility. In comparison, the 6-MWT HRs were 0.434 and 0.544 for mortality and heart failure hospitalisation, respectively (p = < 0.001). Conclusion Prognostic utility of the KCCQ and MLHFQ scores is non-inferior to the 6-MWT in ATTR-CM. While much more simplistic, the EQ-5D is lacking behind the other tested questionnaires with regard to predictive utility.

Effect of timely availability of TTR-stabilizing therapy on diagnosis, treatment initiation, and cardiovascular outcomes in transthyretin amyloid cardiomyopathy

Abstract Background Transthyretin-stabilization reduces cardiovascular morbidity and mortality in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). Despite increased access, regional differences in the availability of therapy continue to exist, and how these may affect diagnostic efficacy and cardiovascular outcomes is currently unknown. Objective To determine how access to and availability of tafamidis affected time-to-diagnosis, time-to-therapy, and cardiovascular outcomes in patients with ATTR-CM. Methods and Results 91 consecutive patients diagnosed with ATTR-CM between June 2019 and June 2021 were evaluated for TTR-stabilizing therapy with tafamidis. Access was regulated by an expanded access program for the initial 42 patients (early cohort; 46.2%), while insurance coverage was required for the latter 49 patients (facilitated access cohort, 53.8%) after local regulatory drug approval in April 2020. Tafamidis was started in 37 of 42 (88.1%), and 43 of 49 patients (87.8%), respectively. Baseline characteristics, e.g., age (76.3±6.4 vs. 77.3±6, p = 0.45), sex (male: 95.2% vs. 93.9%) and ATTR-CM disease stage (≤stage 2: 88.2% vs. 90.9%, p= 0.919) were comparable between both groups. Timely availability of tafamidis after April 2020 numerically reduced time from first presentation to diagnosis (median [months (IQR)]) from 6.2 (1.3;28.9) to 2.4 (0.7; 21.7) months (p = 0.196) and from presentation to therapy from 24.4 (10.7;46.8) to 11.8 (6.4; 32.4) months (p = 0.127). While RV function assessed by echocardiography significantly decreased in the early cohort between diagnosis and therapy initiation (S’ velocity 10±2.2 to 9.2±2.2 cm/s; p = 0.018; TAPSE 17.3±4.7 to 15.7±3.9, p = 0.008) it remained stable in the facilitated access cohort (S’ velocity 9.56±2.57 to 9.36±2.28 cm/s; p = 0.83; TAPSE 15.6±4.2 to 16.3±3.1, p = 0.45). After a median follow-up 42.3 and 24.9 months in the early and facilitated access cohort, respectively, timely availability of tafamidis in the facilitated access cohort was associated with a significant reduction of annual heart failure hospitalisations (treated: 0.12±0.34 vs. 0.5±1, p = 0.049; overall cohort: 0.17±0.37 vs. 0.35±0.47, p = 0.044). Overall, timely diagnosis of ATTR-CM within 12 months of first presentation was associated with a significant reduction in all-cause mortality [HR = 3.490 (95% CI 1.37 to 8.91), p = 0.009], prolonged survival without MACE [HR = 2.50 (95% CI 1.30 to 4.81), p = 0.006] or heart failure hospitalisation [HR = 2.52 (95% CI 1.24 to 5.16), p = 0.011]. Conclusions Availability of tafamidis numerically shortened time-to-diagnosis and time-to-therapy initiation in ATTR-CM patients. Timely diagnosis and initiation of therapy was associated with a reduction in all-cause mortality and heart failure hospitalisations.Door-to-diagnosis-therapyClinical outcomes

Novel SPECT/CT biomarker in transthyretin cardiac amyloidosis: correlation with myocardial amyloid load and cardiac structure and function

Abstract Background Single photon emission computed tomography/computed tomography (SPECT/CT) with determination of standardized uptake value (SUV) allows quantification of cardiac amyloid deposition. Purpose We aimed to investigate the relationship between quantitative cardiac tracer uptake determined by SPECT/CT and myocardial amyloid load, as well as cardiac structure and function in patients with transthyretin amyloid cardiomyopathy (ATTR-CM), and to identify nuclear imaging biomarkers for monitoring disease progression. Methods ATTR-CM patients underwent [99mTc]-radiolabeled diphosphono-1,2-propanodicarboxylic acid ([99mTc]-DPD) scintigraphy and SPECT/CT imaging (n=40) with determination of SUV, as well as cardiac magnetic resonance imaging (CMR, n=25) and transthoracic echocardiography (TTE, n=40). Results We observed significant correlations (r, Pearson's correlation coefficient) between SUV retention index and myocardial amyloid load [CMR extracellular volume (ECV): r=0.565, p=0.004, Figure 1A], cardiac structure [CMR interventricular septum: r=0.409, p=0.042, Figure 1B; CMR left ventricular mass index: r=0.508, p=0.010, Figure 1C], longitudinal cardiac function [TTE left ventricular global longitudinal strain (LV GLS): r=0.531, p=0.003, Figure 1D; TTE right ventricular free wall longitudinal strain: r=0.470, p=0.024, Figure 1E; TTE left atrial reservoir strain (LASr): r=-0.434, p=0.038, Figure 1F] and cardiac biomarkers [N-terminal prohormone of brain natriuretic peptide (NT-proBNP): r=0.475, p=0.004; high-sensitive troponin T (hs-TnT): r=0.358, p=0.027]. ATTR-CM patients were divided into two cohorts based on the median (4.32 mg/dL) of SUV retention index (low SUV uptake cohort: ≤4.32 mg/dL, n=20; high SUV uptake cohort: >4.32 mg/dL, n=20). We observed significant between-cohort differences with respect to LV ejection fraction (low SUV uptake: 51.8% vs. high SUV uptake: 46.2%, p=0.045), LV GLS (-14.5% vs. -11.1%, p=0.001), LASr (11.6% vs. 7.1%, p=0.023), NT-proBNP (1300 pg/mL vs. 2786 pg/mL, p<0.001), hs-TnT (42.9 ng/L vs. 62.2 ng/L, p=0.016) and 6-min walk distance (440.1 m vs. 330.1 m, p=0.022). Conclusions Using quantitative SPECT/CT imaging, we demonstrated that SUV retention index correlates with myocardial amyloid load, cardiac structure and function, and cardiac biomarkers. Our data suggest that quantitative SPECT/CT imaging with determination of SUV retention index may be a valid tool to monitor disease progression in ATTR-CM patients.Figure 1

Transthyretin amyloid cardiomyopathy among patients with hypertrophic cardiomyopathy: clinical, cardiac imaging, and electrocardiographic findings from the TTRACK study

Abstract Background Transthyretin amyloid cardiomyopathy (ATTR-CM) is often misdiagnosed as hypertrophic cardiomyopathy (HCM). Identifying ATTR-CM in patients with HCM is essential because treatment approaches vary, especially with the availability of disease-modifying therapies for ATTR-CM. In this analysis of the TTRACK study, we investigated clinical, cardiac imaging, and electrocardiogram (ECG) features of ATTR-CM that may heighten suspicion of amyloid disease and prompt further screening in patients with HCM. Purpose Explore the clinical, echocardiogram (echo), magnetic resonance imaging (MRI), and ECG findings of patients with HCM screened for ATTR-CM in the TTRACK study. Methods In this global, multicentre, non-interventional epidemiological study, the prevalence of ATTR-CM was assessed in patients ≥50 years of age with HCM of unknown aetiology (left ventricular [LV] maximum wall thickness ≥15 mm [echo]) using 99mTc-DPD/99mTc-PYP/99mTc-HMDP-labeled bone scintigraphy. Nuclear images were graded based on cardiac vs bone radiotracer uptake following the Perugini system. Monoclonal protein testing was performed to exclude light chain amyloidosis. Results Of 766 eligible patients with scintigraphy data, 521 (68.0%) had no cardiac uptake; 37 (4.8%) had low uptake (grade 1); and 208 (27.2%) had moderate/high uptake (grade 2/3). Among patients with moderate/high uptake (cardiac amyloidosis [CA]), 137 (65.9% of patients with CA; 17.9% of the overall cohort) had confirmed ATTR-CM. Comparing NYHA classification of patients with no cardiac uptake vs those with ATTR-CM, 33.8% and 25.0% were asymptomatic (NYHA class I). Marked numerical differences were observed in some echo findings of patients with no cardiac uptake vs ATTR-CM, including mean LV mass index (155.6 vs 177.0 g/m2) and the proportions of patients with preserved apical strain (57.9% vs 74.2%) and concentric hypertrophic pattern (38.8% vs 77.8%) (Table [A]). Although a smaller percentage of patients with ATTR-CM exhibited LV outflow tract (LVOT) obstruction than patients with no cardiac uptake, 12.5% of patients with ATTR-CM had LVOT obstruction (LVOT gradient >30 mmHg). A substantially lower proportion of patients with no cardiac uptake (54.7%) had late gadolinium enhancement on MRI than those with ATTR-CM (84.6%). Notable ECG differences were seen in PR interval (179.4 vs 196.9 ms) and the proportion with poor precordial R wave progression (21.9% vs 47.9%) (Table [B]). Conclusions In the TTRACK study, conducted in the largest cohort of patients with HCM ever screened for ATTR-CM, approximately 18% of patients ≥50 years of age with HCM had findings indicative of ATTR-CM. Noteworthy differences in some clinical, cardiac imaging, and ECG findings were seen between patients with HCM with and without ATTR-CM, but none appeared to be definitive. These findings suggest that broader screening for amyloid disease with scintigraphy should be considered among all patients with HCM.

A biopsy-based pilot clinical study: monitoring the effectiveness of tafamidis treatment of patients with transthyretin amyloid cardiomyopathy

Abstract Background Transthyretin amyloid cardiomyopathy (ATTR-CM) is a rare and progressive disease associated with high mortality. It is caused by the accumulation of TTR amyloid protein in various tissues, including the myocardium. Tafamidis is currently the only approved therapy for ATTR-CM. The results of the phase III ATTR-ACT trial showed lower rates of mortality and hospitalization, besides lower rate of decline for both quality of life (QoL), and 6-minute walk test (6mwt) distance [1]. Whether the reported clinical outcomes represent a change in myocardial ATTR-accumulation and remodeling remains unclear. Here we monitor the clinical outcome and the corresponding myocardial histological changes of tafamidis-treated patients using endomyocardial biopsy (EMB). Methods Eleven patients with EMB-proven ATTR-CM, 10 wild type, 1 hereditary, 9 males, 2 females age= 77±9 years, were prescribed with 61 mg tafamidis once daily indefinitely. The course of the disease was evaluated via EMB, 99mTc-DPD scintigraphy, cardiac magnetic resonance imaging (cMRI), echocardiography, 6mwt, Minnesota QoL questionnaire and serum N-terminal pro brain natriuretic peptide (NT-proBNP) analysis, at baseline and after 321±72 days of treatment (ethics application number EA2/140/16). EMBs were examined via immunohistochemistry and Imaging mass spectrometry. All patients received standard heart failure medications. Paired clinical measurements were compared via paired t test for parametric data or Wilcoxon rank test for non-parametric data. Results Following the course of treatment, EMB ATTR-positive area measured via immunohistochemistry increased by 7.7±9.5% (p<0.05). Myocardial CD3+ and CD68+ cell counts remained within normal limits. The EMB peak intensities of ATTR, collagen and macrophage migration inhibitory factor, measured via imaging mass spectrometry were increased by 23% (AUC= 0.677, p<0.001), 25% (AUC= 0.620, p<0.001) and 18% (AUC= 0.609, p<0.001), respectively. Echocardiography measured left ventricular (LV) ejection fraction and LV end-diastolic diameter, as well as 6mwt distance, QoL and serum NT-proBNP showed no significant changes. cMRI did not show any significant changes in fibrosis/amyloidosis markers (N=9). 99mTc-DPD scintigraphy-derived Perugini score (N=10) improved by one-point in two patients and remained stable in the rest. The New York Heart Association (NYHA) functional class improved in one patient and remained stable in 10/11 patients. Conclusion Our findings demonstrate, for the first time, the persistence of myocardial ATTR-accumulation and remodeling despite a clinically stable disease course. Whether this finding is relevant in terms of disease-progression or indicate a need for more intensive treatment warrants further investigation.

Clinical red flags associated with transthyretin amyloid cardiomyopathy in patients with left ventricular hypertrophy: results of the TTRACK study

Abstract Background Transthyretin amyloid cardiomyopathy (ATTR-CM) is a life-threatening, systemic disorder that results in progressive physical disability, substantially reduced quality of life, and high morbidity and mortality rates. ATTR-CM is an underrecognized cause of increased left ventricular (LV) wall thickness in older adults, and delayed diagnosis can lead to worse clinical outcomes. To facilitate early identification of patients with LV hypertrophy (LVH) at risk for ATTR-CM, greater recognition of diagnostic ‘red flags’ is required. Purpose To determine the association between diagnostic red flags and ATTR-CM in patients with LVH. Methods TTRACK is a multicentre, non-interventional epidemiological study (ClinicalTrials.gov: NCT03842163). Eligible patients were ≥50 years of age and had unexplained LVH (LV maximum wall thickness ≥15 mm [echocardiogram]). After undergoing technetium-99m-DPD/-PYP/-HMDP-labelled bone scintigraphy, scans were categorized by the degree of tracer uptake in the heart; Perugini grades 0, 1, 2 and 3 represented absent, low, moderate and high uptake, respectively. Immunofixation electrophoresis was used to detect monoclonal protein abnormalities; grade 2 and 3 scans without evidence of monoclonal gammopathy were considered diagnostic for ATTR-CM. The frequency of predetermined clinical disease markers was compared in patients without monoclonal protein abnormalities and grade 0 or grade 2/3 scans. Results Of 766 eligible patients with scintigraphy data, 521 (68.0%) had grade 0 cardiac uptake; 37 (4.8%) had grade 1; and 208 (27.2%) had grade 2/3. Among patients with moderate/high uptake, 137 (65.9% of those with grade 2/3 uptake; 17.9% of the overall cohort) had no monoclonal protein abnormalities (ATTR-CM); 56 (26.9%) had monoclonal gammopathy of undetermined significance or light chain amyloidosis; and 15 (7.2%) patients had unknown monoclonal test findings. On univariable analysis, carpal tunnel syndrome (odds ratio [95% CI], 27.7 [16.7, 46.1]), permanent atrial fibrillation (3.4 [2.2, 5.2]), male sex (2.9 [1.8, 4.8]) and advanced heart failure (1.8 [1.2, 2.9]) were the strongest predictors for grade 2/3 scans; on multivariable analysis, carpal tunnel syndrome (50.3 [23.4, 108.0]), male sex (9.1 [3.9, 21.3] and age (1.7 [1.4, 2.1]) were the strongest predictors (Figure). Conclusions In the TTRACK study, 18% of patients ≥50 years of age with unexplained LVH ≥15 mm had ATTR-CM. Carpal tunnel syndrome, male sex and advanced age were associated with a greater likelihood of ATTR-CM.

Impaired left atrial reservoir function associated with large v wave in patients with transthyretin amyloid cardiomyopathy

Abstract Background Impaired atrial function, in addition to ventricular diastolic dysfunction, is one of the hallmarks of cardiac amyloidosis (ATTR-CM). Two-dimensional speckle tracking echocardiography is a useful technique for quantitative assessment of LA stiffness. A large v wave on pulmonary artery wedge (PAW) pressure waveform is the findings suggesting LA overload and impaired LA reservoir function. Although large v waves on PAW pressure waveforms are sometimes observed in ATTR-CM patients, their hemodynamic background and clinical significance have not been well described. Purpose To investigate the clinical importance of LA function obtained by echocardiography and PAW pressure waveform and the association of enhanced large PAW v wave to clinical outcomes in ATTR-CM patients. Methods We retrospectively analyzed central hemodynamics in 136 ATTR-CM patients without severe mitral regurgitation. Large v wave was defined 10 mmHg above mean PAW pressure. We divided 136 ATTR-CM into large v wave group (n = 27) and non-large v wave group (n = 109), and compared the differences in baseline parameters and echocardiographic parameters. Results Patients in the large v wave group showed higher mean PAW pressure (24mmHg vs. 14mmHg, p<0.0001). There were no significant differences in age, prevalence of atrial fibrillation, high-sensitivity cardiac troponin T levels (0.060 ng/ml vs. 0.044 ng/mL, p = 0.341), B-type natriuretic peptide levels (188.3 pg/ml vs. 178.7 pg/mL, p = 0.386). In addition, LV ejection fraction, LA diameter, E/e` and cardiac index showed no significant differences between the two groups. However, LA peak longitudinal strain (LS) and LS rate (LSR), evaluation of LA reservoir function, expressed significant depression in large v wave group (LS: 6.24 % vs 9.21 %, p<0.0001, LSR: 0.29 1/s vs 0.38 1/s, p = 0.005). Conclusions In ATTR-CM patients, the impaired LA reservoir function associated with extent of large v wave on PAW pressure. This result suggested that impaired LA function may be useful for assessing the progression of ATTR-CM and the deterioration of central hemodynamics.

Left ventricular speckle-tracking-derived mechanical dispersion in patients with transthyretin amyloidosis and their first-degree relatives

Abstract Background Mechanical dispersion has shown to predict ventricular (LV) arrhythmias and sudden cardiac death in populations with established cardiac diseases, such as cardiomyopathies and heart failure. Transthyretin amyloid (ATTR) cardiomyopathy arises from deposition of misfolded, insoluble transthyretin (TTR) in extracellular matrix. The disease impacts profoundly cardiac tissue architecture and its mechanical properties. Purpose The aim of this prospective study was assessment of LV speckle-tracking-derived mechanical dispersion in patients with ATTR cardiomyopathy and their first-degree relatives. Methods We present data based on evaluation of 85 patients, including 34 (group 1) index patients with ATTR and 51 (group 2) first-degree relatives who were studied between June 2020 and January 2023. Study protocol included clinical data, free light chain blood immunoglobulins and urine immunofixation, transthoracic echocardiography (TTE) with global longitudinal strain (GLS) analysis, hybrid technique single-photon emission computed tomography and computed tomography (SPECT/CT) with [99mTc] Tc 3,3-disphono-1,2-propanodicarboxylic acid (DPD), genetic testing by an amplicon-based next-generation TTR sequencing approach, and in selected cases cardiac or soft tissue biopsy. Mechanical dispersion was calculated manually from GLS measurements and defined as the standard deviation (SD) of contraction duration from R on the electrocardiogram (ECG) to peak negative longitudinal strain of all LV segments. Results In group 1 patients were older (66.6±11 vs. 50.7±14) and presented with higher New York Heart Association (NYHA) class (2.4± 1 vs. 1.1± 0.6) (p<0.05). Overall, there were detected following types of TTR variants - Phe53Leu, Ala101Val, Glu112Lys, Glu109Lys, Glu122Lys, Glu82Lys. Compared to group 2, group 1 presented with higher N-terminal (NT)-pro hormone BNP (NT-proBNP) value (5859±7320 vs. 281±990 pg/ml), greater intraventricular septum thickness (19±4 vs. 12±3 mm) and LV mass index values (199±69 vs.111±42 g/m2), impaired LV ejection fraction (44±13 vs. 59±10 %) and GLS (-12.7±6 vs. -18.7±4 %) (p<0.05). Moreover, patients with ATTR cardiomyopathy had significantly higher value of LV speckle-tracking-derived mechanical dispersion compared to their first-degree relatives (96.2±22.3 vs. 77.9±23.3 ms, p=0.0007). Conclusions Patients with ATTR cardiomyopathy present with significantly higher LV mass index value, impaired GLS and higher value of LV speckle-tracking-derived mechanical dispersion compared to their first-degree relatives (p<0.05). Assessment of LV speckle-tracking-derived mechanical dispersion may in future translate into further enhancement of disease evaluation and improving prognosis in the group of patients.

Predictive Value of high-sensitivity cardiac troponin T in patients undergoing 99mTc pyrophosphate scintigraphy for suspected transthyretin amyloid cardiomyopathy

Abstract Background Transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly recognized cause of heart failure (1,2). 99mTc- pyrophosphate cardiac scintigraphy (PYP) enables accurate, noninvasive diagnosis of ATTR-CM when coupled with appropriate clinical and laboratory evaluations to rule out light chain amyloidosis (3,4). High sensitivity cardiac troponin T (hs-cTnT) is routinely assessed for diagnostic purposes when ATTR-CM is suspected in clinical practice. Purpose To investigate the diagnostic performance of hs-cTnT in patients undergoing PYP for suspected ATTR-CM. Methods Observational study of patients undergoing PYP at a United States (US) cardiac amyloidosis referral center from 2013 to September 2022 and with at least one hs-cTnT value available within 1 year. 3-hour planar imaging followed by single photon-emission computed tomography with computed tomography was performed. Final diagnoses of ATTR-CM were validated using all clinical information. The lowest reportable clinical value for hs-cTnT in the US is <6 ng/L (limit of quantitation). Results A total of 1572 patients underwent PYP and had a hs-cTnT value available within the study period. Of these, ATTR-CM was diagnosed in 475 patients (30%). Median (IQR) hs-cTnT was 48 (31-67) ng/L in patients with ATTR-CM and 26 (13-48) ng/L in those without. The area under the curve of hs-cTnT for the diagnosis of ATTR-CM was 0.69 (0.67-0.72). Among patients with a very low hs-cTnT value, i.e. <6 ng/L (n=100, 6.4% of the overall cohort), 7 (7%) patients had a final ATTR-CM diagnosis while 93 (93%) did not. Therefore, a threshold of <6 ng/L demonstrated a negative predictive value (NPV) of 93% (IQR 88, 98) and a sensitivity of 99% (97, 100) for ruling out ATTR-CM. The highest NPV was achieved with a threshold of 12 ng/L; 269 (17%) patients had hs-cTnT below this value and, of those, only 16 (6%) had a final diagnosis of ATTR-CM. This resulted in a NPV of 94% (91, 97) and a sensitivity of 97% (95, 98) for ruling out ATTR-CM. When considering progressively increasing hs-cTnT values as potential thresholds to aid in the prediction of ATTR-CM (Figure), we observed a progressive increase in specificity (above 90% for hs-cTnT values > 95 ng/L), but the positive predictive value (PPV) remained low (below 50%). Conclusions Among patients undergoing PYP for suspected ATTR-CM at a US referral center, a very low hs-cTnT value was present in a minority of patients but demonstrated good performance in ruling out ATTR-CM. The highest NPV (94%) was achieved with a threshold of < 12 ng/L. Higher hs-cTnT values showed a good specificity, but PPV remained low. Therefore, while a very low hs-cTnT might be of help in identifying those at low risk of ATTR-CM, the ubiquitous presence of increased hs-cTnT in many of these patients suggests the need for a multiparametric diagnostic approach to make the diagnosis.hs-cTnT in patients undergoing PYP scan

Monitoring patisiran and inotersen treatment with quantitative SPECT/CT in hereditary transthyretin amyloid cardiomyopathy

Abstract Background Novel ribonucleic acid interference (RNAi) therapeutics such as patisiran and inotersen have been shown to benefit neurologic disease course and quality of life in patients with hereditary transthyretin amyloidosis (ATTRv). Purpose We aimed to determine treatment effects on myocardial amyloid load determined by quantitative single photon emission computed tomography/computed tomography (SPECT/CT) in patients with ATTRv-related cardiomyopathy (ATTRv-CM) and to identify nuclear imaging biomarkers to quantify and monitor response to therapy. Methods ATTRv-CM patients underwent [99mTc]-radiolabeled diphosphono-1,2-propanodicarboxylic acid ([99mTc]-DPD) scintigraphy and SPECT/CT imaging before and after 12 months of treatment with patisiran (n=5) or inotersen (n=4). Results Patisiran-treated patients had a significant reduction in cardiac uptake as measured by standardized uptake values (SUVpeak: 7.98 g/mL ±0.87 vs. 6.50 g/mL ±1.59, p=0.025, Figure 1A; SUVmax: 8.80 g/mL ±0.94 vs. 6.96 g/mL ±1.59, p=0.009, Figure 1B; SUVmean: 5.64 g/mL ±1.01 vs. 4.42 g/mL ±1.26, p=0.016, Figure 1C). Patients treated with inotersen showed evidence of stabilization in cardiac SUV uptake (SUVpeak: 8.56 g/mL ±2.25 vs. 7.99 g/mL ±1.90, p=0.665; SUVmax: 9.29 g/mL ±2.39 vs. 8.79 g/mL ±2.03, p=0.719; SUVmean: 5.07 g/mL ±1.46 vs. 4.86 g/mL ±0.95, p=0.834) but had significant deterioration in left ventricular (LV) function (LV cardiac index: 3.39 L/min/m2 ±0.04 vs. 2.94 L/min/m2 ±0.01, p=0.028, Figure 1D). Comparison of cardiac SUV uptake and longitudinal cardiac function revealed significant correlations between longitudinal changes in cardiac SUVpeak and LV global longitudinal strain (r=-0.658, p=0.027, Figure 1E) and right ventricular free wall longitudinal strain (r=-0.771, p=0.008, Figure 1F). Conclusions In conclusion, using serial quantitative SPECT/CT imaging, we demonstrated that patisiran treatment significantly reduces cardiac SUV uptake in ATTRv-CM patients, indicating regression of cardiac TTR amyloid. Our data suggest that quantitative SPECT/CT imaging may be a valid tool to quantify and monitor response to disease-specific RNAi therapeutic agents in ATTRv-CM patients.Figure 1Graphical Abstract

The use of 99mTc-PYP SPECT/CT in monitoring therapeutic changes of eplontersen in patients with hereditary transthyretin cardiomyopathy

Abstract Objective Hereditary transthyretin amyloid cardiomyopathy (hATTR-CM) is a progressive and fatal disease. Emerging data suggests the potential role of technetium-99m (99mTc)-pyrophosphate (PYP) scintigraphy to monitor the efficacy of ATTR-CM treatment. We aimed to determine whether eplontersen treatment alters the quantitative uptake of 99mTc-PYP in patients with ATTR-CM. Methods We analyzed a prospective cohort of hATTR-CM patients receiving eplontersen (45 mg/4 weeks). Patients with hATTR-CM who had not received eplontersen, inotersen, tafamidis or patisiran were identified retrospectively as the control group. 99mTc-PYP single-photon emission computed tomography/computed tomography (SPECT/CT) was performed at baseline and at 1 to 2 years later. Volumetric heart to lung (H/L) ratio was measured. Results Thirteen hATTR-CM patients were enrolled, of whom six received eplontersen and the other seven patients were enrolled as the control group. The median follow-up time was 544 days. A significant decrease in volumetric H/L ratio (3.774 ± 0.474 to 2.979 ± 0.354, p = 0.028) after eplontersen treatment was noted in the eplontersen group, while there was no significant change (4.141 ± 0.557 to 3.915 ± 0.3864, p = 0.237) in the control group. Comparing the two groups, the patients who received eplontersen showed a significantly greater decrease in volumetric H/L ratio compared to the control group (-20.7% ± 7.8% vs -3.4% ± 8.1%, p = 0.007). Conclusion 99mTc-PYP uptake measured by volumetric H/L ratio significantly decreased after eplontersen treatment in patients with hATTR-CM. Our results suggest the effectiveness of eplontersen in patients with hATTR-CM and the role of 99mTc-PYP SPECT/CT to monitor the efficacy of eplontersen treatment.Workflow of volumetric H/L ratioChanges in volumetric H/L ratio

Predictors of disease burden in patients with untreated transthyretin amyloid cardiomyopathy: post hoc analysis of an international survey study

Abstract Background Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive condition that can cause debilitating symptoms.[1] The burden of untreated ATTR-CM was recently evaluated in an international, multicentre, real-world survey study.[2] Identifying predictors of ATTR-CM burden can help improve patients’ therapeutic journey. Purpose To identify predictors of disease burden on patients with ATTR-CM treated with symptomatic but not disease-modifying therapy using data from the recent international real-world survey study. Methods The original study surveyed 208 patients with untreated ATTR-CM recruited from international amyloidosis centres of excellence in 7 countries between July 2021 and August 2022. This post hoc analysis used univariate and multivariate models to evaluate selected survey variables as predictors of patient burden. Variables and outcomes included in the models are described in the figure. Univariate associations were confirmed with a t-test and Pearson correlation coefficient. The full multivariate models included all variables and were then optimised using forward selection and CV Press criteria with 8-fold cross-validation to identify the best predictors. Results The patient population in the original study were generally male (86%) and elderly (median 81 [range: 46 – 90] years), with wild-type ATTR-CM (91% of 155 with genetic testing; median time since diagnosis: 6 months). Of the 199 patients with a recorded NYHA classification, 60% were class II, 22% were class III, 18% were class I, and none were class IV. The investigator reported each neurologic symptom variable (Figure) as a current symptom in 25–41 patients, and gastrointestinal or urinary problems in 36 patients. Out-of-pocket expenses in the prior 3 months were reported by 78 patients. Respective median (IQR) KCCQ-OS, -CS and -TS scores were 67.7 (46.4–84.4; n = 183), 69.0 (49.5–87.5; n = 202), and 75.0 (52.1–91.7; n = 208); HADS-A and HADS-D scores were 5.0 (3.0–8.0; n = 205), and 6.0 (3.0–10.0; n = 204); SF-12 PCS and MCS scores were 36.3 (27.5–43.5; n = 206) and 46.8 (39.4–54.4; n = 206); and PROMIS Fatigue T-score was 50.8 (45.8–57.8; n = 203). In the unadjusted univariate models, NYHA class and the neurologic symptom variable of weakness, especially in the legs, were independently associated with all outcome measures of burden. Closely reflecting the statistically significant predictors in the full multivariate models, older age (continuous or age over 80 years), symptomatic heart failure (NYHA class II or III), female sex, and having weakness, especially in the legs, were among the best predictors of a higher burden in several optimized models (Table). Conclusions In this study of patients with ATTR-CM receiving symptomatic but not disease-modifying therapy, our analysis suggests that older age, female sex, and cardiac or neurologic symptoms are often predictors of higher disease burden.Figure:Variables and outcome measuresTable:Optimised models

Tafamidis Efficacy Among Octogenarian Patients in the Phase 3 ATTR-ACT and Ongoing Long-Term Extension Study

BackgroundTafamidis was approved to treat patients with transthyretin amyloid cardiomyopathy (ATTR-CM) on the basis of findings from the phase 3 Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT). ObjectivesThis study was a post hoc analysis exploring tafamidis efficacy in octogenarian patients. MethodsAnalysis of patients aged <80 and ≥80 years in ATTR-ACT and its ongoing open-label long-term extension (LTE) study, where all patients receive tafamidis. ResultsAfter 30 months in ATTR-ACT, least squares (LS) mean change from baseline in 6-minute walk test (6MWT) distance, N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration, and Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) score were smaller (all P < 0.05) in patients aged ≥80 years treated with tafamidis (n = 51) vs placebo (n = 37). At the LTE study interim analysis, patients aged ≥80 years treated continuously with tafamidis had a smaller decline in KCCQ-OS score (P < 0.05) and trended toward longer median survival (45 vs 27 months; all-cause mortality HR: 0.6828 [95% CI: 0.4048-1.1517]; P = 0.1526) than those initially treated with placebo in ATTR-ACT. Similar efficacy was observed in patients aged <80 years in ATTR-ACT, including smaller LS mean change from baseline in 6MWT distance, NT-proBNP concentration, and KCCQ-OS score, and lower rate of cardiovascular-related hospitalizations with tafamidis (n = 125) vs placebo (n = 140). In the LTE study, patients aged <80 years treated continuously with tafamidis had a longer median survival (80 vs 41 months; HR = 0.4513 [95% CI: 0.3176-0.6413]; P < 0.0001) and a smaller decline in KCCQ-OS score than those initially treated with placebo. ConclusionsThe findings demonstrate tafamidis efficacy for patients with ATTR-CM both in those aged <80 and those aged ≥80 years. (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial [ATTR-ACT]; NCT01994889/Long-term Safety of Tafamidis in Subjects With Transthyretin Cardiomyopathy; NCT02791230)

Abstract 16990: Empagliflozin Therapy is Associated With Improved Left Ventricular Diastolic Function in Patients With Transthyretin Amyloid Cardiomyopathy

Introduction: Although SGLT-2 inhibitors demonstrated beneficial clinical effects in patients with heart failure with preserved ejection fraction, their role in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) remains undefined. Hypothesis: We investigated the effects of empagliflozin on myocardial function in patients with ATTR-CM. Methods: In a prospective single-center non-randomized cohort study we enrolled 15 consecutive patients with ATT-CM receiving tafamidis 61 mg qd and standard heart failure therapy for at least six months prior to enrolment. At the time of inclusion, all patients started receiving empagliflozin 10 mg qd. Biochemical and echocardiographic parameters were evaluated at baseline and again at 6-months. Results: At the time of inclusion, the average age of patients was 74.8±5.7 years, 14 (93%) were male, and 14 (93%) had NYHA class II symptoms; 10 (67%) patients were receiving ARNI/ACEI/ARB, 5 (33%) were treated with beta blockers, and 3 (20%) were receiving mineralocorticoid receptor antagonists. At 6-months follow-up we found no change in NT-proBNP levels (1694±1237 ng/L at baseline vs. 1549±1203 ng/L at follow up; P=0.78), hs-Troponin I levels (33±19 ng/L vs. 39±26 ng/L; P=0.50), or eGFR (65.9±14.4 mL/min vs. 64.9±14.8 mL/min; P=0.87). Furthermore, we observed no changes in LVEDV (84±19 mL vs. 88±17 mL; P=0.61), LVEF (57±8% vs. 57±7%; P=0.94), LV mass (265±74 g vs. 279±88 g; P=0.67), or RVIDd (39±8 mm vs. 36±7 mm; P=0.39). However, at 6 months we found a significant decrease in E/e’ (19.2±5.1 vs. 14.9±5.4; P=0.05). When stratifying patients according to the baseline E/e’ value we found a significant improvement of right ventricular FAC (44.1±6.2% vs. 31.9±8.9%; P=0.04) and TR pressure gradient (26.0±5.7 mmHg vs. 39.7±5.2 mmHg; P=0.04) in patients with E/e’ below median compared to patients with E/e’ above median value. Conclusion: In patients with ATTR-CM, empagliflozin therapy appears to reduce left ventricular filling pressures and may be associated with improved right ventricular systolic function in a subset of this patient population.

Abstract 12381: De Novo Multiple Myeloma in a Patient With Transthyretin Amyloid Cardiomyopathy

Background: The development of de novo multiple myeloma in a patient with transthyretin amyloid cardiomyopathy (ATTR-CM) is rare and is often associated with poor prognosis. Early and definitive diagnosis is crucial to improve survival. Case: A 63-year-old male was evaluated for heart failure. He had a history of hypertension, sick sinus syndrome status post dual chamber pacemaker, non-sustained ventricular tachycardia requiring ablation in addition to bilateral carpal tunnel syndrome, spontaneous biceps tendon rupture, and lumbar spinal stenosis. Transthoracic echocardiogram showed progressive severe left ventricular hypertrophy with a septal thickness of 2.0cm with a normal left ventricular ejection fraction. Decision-Making: Given his history, an amyloid evaluation was performed. Serum and urine assessment for light chain amyloidosis revealed elevated kappa free light chains with kappa/lambda free light chain ratio of 19.30. Bone marrow biopsy at that time showed normocellular bone marrow with less than 3% plasma cells. An abdominal fat pad biopsy was inconclusive. A cardiac MRI was unobtainable given non-compatible pacemaker leads and a technetium-99m pyrophosphate scintigraphy was deferred given his abnormal light chains. An endomyocardial biopsy was performed and revealed wild-type ATTR deposition by mass spectrometry. Serum genetic test confirmed the absence of TTR gene mutation. The patient was started on Tafamadis. Six months later, he was noted to have progressive elevation in kappa free light chains on serial evaluation and underwent a repeat bone marrow biopsy. This showed plasma cell myeloma with 25-30% marrow cellularity and flow cytometry consistent with kappa light chain multiple myeloma. He was started on Daratumumab, Lenalidomide, and Dexamethasone. This resulted in normalization of his free light chain ratio and morphologic remission on repeat bone marrow biopsy. Conclusion: In patients who are found to have monoclonal gammopathy, an endomyocardial biopsy is crucial to evaluate for amyloid cardiomyopathy. These patients should also be monitored for the progression to multiple myeloma.

Abstract 18202: Sex Differences in Transthyretin Amyloid Cardiomyopathy

Introduction: Transthyretin amyloid cardiomyopathy (ATTR-CM) predominantly affects men. It is unknown if women are underdiagnosed or if female sex is protective. We investigated sex differences in clinical presentation and disease outcomes in ATTR-CM. Methods: Patients seen with ATTR-CM at our institution were included for analysis. Chi-squared or Fisher’s exact tests, and Wilcoxon tests were used to assess associations between clinical variables and sex in the overall cohort as well as by genotype (wtATTR and V122I). Hazard ratios with 95% confidence intervals were used to assess outcomes. Results: Of 293 subjects, 235 (80%) were men and 58 (20%) were women. Women vs men were more likely Black in the entire cohort (65% v 39%) and in the wtATTR group (70% v 8.7%, p&lt;0.05). Women were significantly older in wtATTR (84 [6.6] v 79 [7.2] yrs) and V122I (75 [6] v 71 [8.3] yrs), had higher HR (83 v 75 bpm), lower eGFR (54 v 62 mL/min/1.73 m2), and thinner intraventricular septum diameter (1.54 [0.3] v 1.71 [0.3] cm) than men at time of diagnosis (p&lt;0.05). Women with wtATTR had significantly higher mean RAP (14.8 [6.9] v 8.69 [4.8] v mmHg, p&lt;0.05) and a trend toward higher PASP (55.5 [17.0] v 42.9 [12.8] and PCWP (22.5 [6.7] v 17.3 [6.4] mmHg, p=0.06) vs men. There was no difference in HF hospitalization or death at 5 years (HR 0.93 [0.59-1.45], p=0.70) and no significant increase in proportion of women diagnosed over disease eras (pre-2013, 2013-2018, and 2019-2023). Conclusions: In a well characterized cohort with ATTR-CM, women were diagnosed less frequently and at an older age with markers of more advanced disease including higher HR, worse renal function, and higher filling pressures compared to men. Disease recognition in women did not increase over time. While this may be due to the nature of the disease, the characteristics we identified at diagnosis support that women with ATTR-CM are under detected. Future sex-based screening studies are needed to increase detection of ATTR-CM in women.

Abstract 17332: Length of Diagnosis, Diagnostic Tests, and Referral Patterns of Transthyretin Amyloid Cardiomyopathy Patients in the United States, United Kingdom, France, Germany, Italy, and Spain

Introduction: Transthyretin amyloid cardiomyopathy (ATTR-CM) is a rare disease that typically presents with symptoms like those commonly associated with heart failure and is frequently misdiagnosed. Timely diagnosis and treatment are key to a favorable prognosis. This study aims to investigate and compare the length between suspicion of ATTR-CM and confirmed diagnosis, examine the number of diagnostic tests, and explore the referral dynamics in the US versus EU4+UK (United Kingdom, France, Germany, Italy, and Spain) using real-world data among patients diagnosed in 2022. Methods: A multi-center online medical chart review of patients was fielded in Q4’2022. Cardiologists and cardiology-focused internists from the US and EU4+UK from hospitals and private practices were recruited and screened for ATTR-CM patient management. A total of 239 physicians (US: 109, EU5: 130) who reported on patients diagnosed in 2022 were included, providing data on 759 patients diagnosed during this period (US: 481, EU5: 278). Results: Reported patients in the US experienced a shorter length of time from first suspicion of ATTR-CM to confirmed diagnosis, on average, than those in the EU4+UK (p&lt;0.01); US: 6.3 weeks (n=392), EU4+UK: 9.6 weeks (n=205). The average number of tests ordered to diagnose patients was greater in the EU4+UK than in the US cohort (p&lt;0.01); EU4+UK: 6.8 tests (n=277), US: 5.8 tests. A greater proportion of reported patients in the US (p&lt;0.05) first presented their symptoms prior to diagnosis to the reporting physician (35.1%) than those in EU4+UK (27.3%). In the US, 88.4% of the patients were diagnosed by the reporting physician (n=481), whereas in EU4+UK (n=278) this rate was 78.1% (p&lt;0.01). Conclusions: This study demonstrated that it took significantly less time to diagnose patients in 2022 in the US than in the EU4+UK. Patients in the EU4+UK were more likely to present symptoms to and be diagnosed by a physician other than the reporting physician, with a greater number of diagnostic tests ordered compared to those in the US. Further investigation using comparator cohort and to discover if there is a difference in patient outcomes is warranted.

Abstract 17038: Mineralocorticoid Antagonist Use for Transthyretin Amyloid Cardiomyopathy and Associated Outcomes

Background: Diuretics have been the mainstay of symptomatic treatment for patients with amyloid cardiomyopathy however, there remains no established guideline directed medical therapy for this population. The anti-fibrotic properties of mineralocorticoid antagonists (MRA) are intriguing for potential use in transthyretin amyloid cardiomyopathy (ATTR CM); while they have shown promise for treatment of patients with heart failure with preserved ejection fraction, their use has never been studied specifically in the ATTR CM population. The purpose of our study is to evaluate the real-world use of MRA and associated outcomes in patients with ATTR CM at a large cardiac amyloid treatment center. Methods: Between 2009 and 2023, 168 patients with ATTR CM at our center were assessed for history of MRA use. Biomarkers, including baseline levels of troponin and natriuretic peptides, as well as kidney function were assessed. We also assessed the outcomes of 5-year survival, need for heart transplant, hospitalization, and mechanical circulatory support (MCS) use. Results: Of the 168 patients, 49 (29%) had a history of MRA use and 119 (71%) had no prior use. Between the two groups, there was no significant difference in age, frequency of ATTR CM subtype, kidney disease, or biomarker level at the time of diagnosis. While 5-year survival and need for MCS were similar between the two groups, there was a higher rate of transplant and hospitalization in the MRA use group. Conclusion: In a cohort of patients with ATTR CM, MRA use is uncommon and was not associated with improved outcomes. It was associated with higher rates of hospitalizations and heart transplantation; however, this may represent confounding by indication. Future investigations with larger registry cohorts and randomized control trials are warranted for further evaluation of biological and clinical effect of MRA use.

Abstract 13079: Prevalence and Incidence of Transthyretin Amyloid Cardiomyopathy in the USA From 2004 to 2022: An Observational Database Study

Introduction: Improved diagnosis and awareness have resulted in global increases in the incidence and prevalence of transthyretin amyloid cardiomyopathy (ATTR-CM). However, current US epidemiology data are lacking. Aims: To estimate the prevalence and incidence of ATTR-CM in a large US population and describe characteristics of patients with ATTR-CM. Methods: Data from 2004–2022 were extracted from TriNetX, a US database of EMRs covering in- and outpatient data. An algorithm using ICD-9/10 codes and RxNorm codes for clinical drugs (amyloidosis + cardiac manifestation – light chain amyloidosis) was used to identify patients with ATTR-CM. Included were adults ≥ 18 years old at index date (first ATTR-CM diagnosis per the algorithm) with ≥ 1 year of database history. The incidence and prevalence of ATTR-CM were assessed annually. Demographic characteristics at index and ATTR-CM-related comorbidities any time pre-index were assessed in cross-sectional cohorts over time. Results: In total, 12 209 patients were identified (2004–08, n = 332; 2009–13, n = 913; 2014–18, n = 3392; 2019–22, n = 7572). The incidence and prevalence of ATTR-CM per 100 000 people increased over time (incidence, 2004: 3.7; 2022: 11.5; prevalence, 2004: 5.1; 2022: 35.1) ( Figure ). Across cohorts, approximately 40% of patients were women, and 20% were Black. Median age increased over time (2004–08: 65 years; 2019–22: 74 years). In the 2019–22 cohort, the cardiac manifestations of ATTR-CM were cardiomyopathy (56.3%), atrial fibrillation (56.1%), and heart failure (20.9%). The proportion of patients with ATTR-CM-related comorbidities increased over time (2004–08 vs 2019–22: polyneuropathy, 15.1 vs 19.0%; carpal tunnel syndrome, 10.5 vs 13.4%; lumbar spinal stenosis, 4.2 vs 13.3%; aortic stenosis, 9.3 vs 13.2%). Conclusion: In this US population, the incidence and prevalence of ATTR-CM diagnoses increased over 19 years. Age at diagnosis and ATTR-CM comorbidity burden increased during this period.