Internalisation of immunoglobulin light chains by cardiomyocytes in AL amyloidosis: what can biopsies tell us?

BACKGROUND: Cardiac involvement in systemic light chain amyloidosis (AL) leads to chronic heart failure and is a major prognosis factor. Severe cellular defects are provoked in cardiac cells by tissue-deposited amyloid fibrils of misfolded free immunoglobulin light chains (LCs) and their prefibrillar oligomeric precursors. OBJECTIVE: Understanding the molecular mechanisms behind cardiac cell cytotoxicity is necessary to progress in therapy and to improve patient management. One key question is how extracellularly deposited molecules exert their toxic action inside cardiac cells. Here we searched for direct evidence of amyloid LC uptake by cardiomyocytes in patient biopsies. METHODS: We immunolocalized LCs in cardiac biopsies from four AL cardiac amyloidosis patients and analysed histopathological images by high resolution confocal microscopy and 3D image reconstruction. RESULTS: We show, for the first time directly in patient tissue, the presence of LCs inside cardiomyocytes, and report their proximity to nuclei and to caveolin-3-rich areas. Our observations point to macropinocytosis as a probable mechanism of LC uptake. CONCLUSIONS: Internalisation of LCs occurs in patient cardiomyocytes. This event could have important consequences for the pathogenesis of the cardiac disease by enabling interactions between amyloid molecules and cellular organelles inducing specific signalling pathways, and might bring new insight regarding treatment.

Phenotype and prognostic factors in geriatric and non-geriatric patients with transthyretin cardiomyopathy.

AIMS: Transthyretin cardiac amyloidosis (ATTR-CM) may be an underestimated cause of heart failure among geriatric patients and represent a unique phenotype and prognostic profile. METHODS AND RESULTS: This retrospective, observational, cohort study characterizes cardiac and extracardiac disorders at diagnosis and assesses prognosis among ATTR-CM patients based on age (geriatric vs. non-geriatric) and amyloidosis subtype (wild type, ATTRwt and hereditary, ATTRv). In total, 943 patients with ATTR-CM were included, of which 306 had ATTRv and 637 had ATTRwt. Among these, 331 (35.1%) were non-geriatric (<75 years), and 612 (64.9%) were geriatric (≥75 years). The population exhibited conduction abnormalities, atrial fibrillation and ischaemic heart disease that progressively deteriorated with age. Among ATTRwt patients, peripheral neuropathy, neurovegetative symptoms, and hearing loss were present across all age groups, but reports of carpal tunnel symptoms or surgery decreased with age. Conversely, among ATTRv patients, reports of extracardiac symptoms increased with age and Val122ILe mutation was highly prevalent among geriatric patients. The 3-year survival was higher among non-geriatric ATTR-CM patients (76%) than geriatric patients (55%) and predictors of 3-year mortality differed. Notably, predictors identified among geriatric patients were alkaline phosphatase (ALP) (HR = 1.004, 95% CI: [0.001-1.100)], troponin T hs (HR = 1.005, 95% CI: [1.001-1.120)] and tricuspid insufficiency (HR = 1.194, 95% CI: [1.02-1.230)]. Whereas, among non-geriatric patients, NT-proBNP (HR = 1.002, 95% CI: [1.02-1.04], global longitudinal strain (HR = 0.95, 95% CI: [0.922-0.989], and glomerular filtration rate (HR = 0.984, 95% CI: [0.968-1.00) were identified. We propose a 3-stage prognostic staging system combining troponin T hs (≥44 ng/L) and ALP levels (≥119 UI/L). In the geriatric population, this model discriminated survival more precisely than the National Amyloidosis Centre staging, particularly for classifying between stage 1 (82%), stage 2 (50%) and stage 3 (32%) for ATTRv and ATTRwt. CONCLUSIONS: These diagnostic and prognostic indicators, along with ATTR subtype, highlight the distinct characteristics of this important, geriatric ATTR-CM patient group. Recognizing these mortality markers can be valuable for geriatricians to improve the prognostic quality management of geriatric patients with ATTR-CM.

Prevalence, Characteristics, and Impact on Prognosis of Aortic Stenosis in Patients With Cardiac Amyloidosis.

BACKGROUND: Cardiac amyloidosis (CA) is frequently found in older patients with aortic stenosis (AS). However, the prevalence of AS among patients with CA is unknown. The objective was to study the prevalence and prognostic impact of AS among patients with CA. METHODS AND RESULTS: We conducted a retrospective analysis of a prospective registry comprising 976 patients with native aortic valves who were confirmed with wild type transthyretin amyloid (ATTRwt), hereditary variant transthyretin amyloid (ATTRv), or immunoglobulin light-chain (AL) CA. CA patients' echocardiograms were re-analyzed focusing on the aortic valve. Multivariable Cox regression analysis was performed to assess the mortality risk associated with moderate or greater AS in ATTRwt CA. The crude prevalence of AS among patients with CA was 26% in ATTRwt, 8% in ATTRv, and 5% in AL. Compared with population-based controls, all types of CA had higher age- and sex-standardized rate ratios (SRRs) of having any degree of AS (AL: SRR, 2.62; 95% Confidence Interval (CI) [1.09-3.64]; ATTRv: SRR, 3.41; 95%CI [1.64-4.60]; ATTRwt: SRR, 10.8; 95%CI [5.25-14.53]). Compared with hospital controls, only ATTRwt had a higher SRR of having any degree of AS (AL: SRR, 0.97, 95%CI [0.56-1.14]; ATTRv: SRR, 1.27; 95%CI [0.85-1.44]; ATTRwt: SRR, 4.01; 95%CI [2.71-4.54]). Among patients with ATTRwt, moderate or greater AS was not associated with increased all-cause death after multivariable adjustment (hazard ratio, 0.71; 95%CI [0.42-1.19]; P=0.19). CONCLUSIONS: Among patients with CA, ATTRwt but not ATTRv or AL is associated with a higher prevalence of patients with AS compared with hospital controls without CA, even after adjusting for age and sex. In our population, having moderate or greater AS was not associated with a worse outcome in patients with ATTRwt.

Catheter ablation of atrial arrhythmias in cardiac amyloidosis: Impact on heart failure and mortality.

BACKGROUND: Atrial arrhythmias (AA) commonly affect patients with cardiac amyloidosis (CA) and are a contributing risk factor for the development of heart failure (HF). This study sought to investigate the long-term efficacy and impact of catheter ablation on HF progression in patients with CA and AA. METHODS: Thirty-one patients with CA and AA undergoing catheter ablation were retrospectively included (transthyretin-ATTR CA 61% and light chain-AL CA 39%). AA subtypes included atrial fibrillation (AFib) in 22 (paroxysmal in 10 and persistent in 12), atrial flutter (AFl) in 17 and atrial tachycardia (AT) in 11 patients. Long-term AA recurrence rates were evaluated along with the impact of sinus rhythm (SR) maintenance on HF and mortality. RESULTS: AA recurrence was observed in 14 patients (45%) at a median of 3.5 months (AFib n = 8, AT n = 6, AFl = 0). Post-cardioversion, medical therapy or catheter ablation, 10 patients (32%) remained in permanent AA. Over a median follow-up of 19 months, all-cause mortality was 39% (n = 12): 3 with end-stage HF, 5 due to late complications of CA, 1 sudden cardiac death, 1 stroke, 1 COVID 19 (and one unknown). With maintenance of SR following catheter ablation, significant reductions in serum creatinine and natriuretic peptide levels were observed with improvements in NYHA class. Two patients required hospitalization for HF in the SR maintenance cohort compared to 5 patients in the AA recurrence cohort (p = 0.1). All 3 patients with deaths secondary to HF had AA recurrence compared to 11 out of the 28 patients whom were long-term survivors or deaths not related to HF (p = 0.04). All-cause mortality was not associated with AA recurrence. CONCLUSION: This study demonstrates moderate long-term efficacy of SR maintenance with catheter ablation for AA in patients with CA. Improvements in clinical and biological status with positive trends in HF mortality are observed if SR can be maintained.

Prognostic mortality factors in advanced light chain cardiac amyloidosis: A prospective cohort study.

AIMS: Predicting mortality in severe AL cardiac amyloidosis is challenging due to elevated biomarker levels and limited thresholds for stratifying severe cardiac damage. METHODS AND RESULTS: This prospective, observational, cohort study included de novo, confirmed cardiac AL amyloidosis patients at the Henri Mondor National Reference Centre. The goal was to identify predictors of mortality to enhance prognostic stratification and improve informed decision-making regarding therapy. Over the 12-year study period, among the 233 patients included, 133 were NYHA III-IV and 179 Mayo 2004 III. The independent predictors for mortality identified were hsTnT, NT-proBNP, cardiac output, and conjugated bilirubin. A novel prognostic, conditional stratification, Mondor amyloidosis cardiac staging (MACS) was developed with biomarker cut-off values for Stage 1: hsTnT ≤ 107 ng/L and NT-proBNP ≤ 3867 ng/L (n = 77; 33%); for stage 2 NT-proBNP > 3867 ng/L (n = 72; 30%). For stage 3, if troponin >107 ng/L, regardless of NT-proBNP then CB 4 µmol/L, was added (n = 41; 17.5%) and stage 4: CB > 4 µmol/L (n = 43; 18.5%). The median overall survival was 8 months 95% CI [2-24]. At 1 year, 102 (44%) patients died and the Kaplan-Meier median survival with MACS Stage 1 was not reached, while stage 2 was 15.2 months (95% CI [11-18]) and stage 3, 6.6 months (95% CI [1-13]). Notably, among European stage II patients, 17.1%, n = 8 were MACS stage 3 and European stage IIIb 21.4% (n = 23) were MACS stage 4. Importantly, among European stage IIIb patients 42.2% (n = 29) were classified MACS stage 4 and 12.5% n = 9 were only MACS stage 2. CONCLUSIONS: The Mondor prognostic staging system, including conjugate bilirubin may significantly improve prognostic stratification for patients with severe cardiac amyloidosis.

Incidence and survival of transthyretin amyloid cardiomyopathy from a French nationwide study of in- and out-patient databases.

BACKGROUND: Precise data about ATTR-CM incidence rates at national level are scarce. Consequently, this study aimed to estimate the annual incidence and survival of transthyretin amyloid cardiomyopathy (ATTR-CM) in France between 2011 and 2019 using real world data. We used the French nationwide exhaustive data (SNDS database) gathering in- and out-patient claims. As there is no specific ICD-10 marker code for ATTR-CM, diagnosis required both amyloidosis (identified by E85. ICD-10 code or a tafamidis meglumine delivery) and a cardiovascular condition (identified by ICD-10 or medical procedure codes related to either heart failure, arrhythmias, conduction disorders or cardiomyopathies), not necessarily reported at the same visit. Patients with probable AL-form of amyloidosis or probable AA-form of amyloidosis were excluded. RESULTS: Between 2011 and 2019, 8,950 patients with incident ATTR-CM were identified. Incidence rates increased from 0.6 / 100,000 person-years in 2011 to 3.6 / 100,000 person-years in 2019 (p < 0.001), reaching 2377 new cases in 2019. Sex ratios (M/F) increased from 1.52 in 2011 to 2.23 in 2019. In 2019, median age at diagnosis was 84.0 years (85.5 for women and 83.5 for men). Median survival after diagnosis was 41.9 months (95% CI [39.6, 44.1]). CONCLUSIONS: This is the first estimate of nationwide ATTR-CM incidence in France using comprehensive real-world databases. We observed an increased incidence over the study period, consistent with an improvement in ATTR-CM diagnosis in recent years.

Patisiran Treatment in Patients with Transthyretin Cardiac Amyloidosis.

BACKGROUND: Transthyretin amyloidosis, also called ATTR amyloidosis, is associated with accumulation of ATTR amyloid deposits in the heart and commonly manifests as progressive cardiomyopathy. Patisiran, an RNA interference therapeutic agent, inhibits the production of hepatic transthyretin. METHODS: In this phase 3, double-blind, randomized trial, we assigned patients with hereditary, also known as variant, or wild-type ATTR cardiac amyloidosis, in a 1:1 ratio, to receive patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks for 12 months. A hierarchical procedure was used to test the primary and three secondary end points. The primary end point was the change from baseline in the distance covered on the 6-minute walk test at 12 months. The first secondary end point was the change from baseline to month 12 in the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score (with higher scores indicating better health status). The second secondary end point was a composite of death from any cause, cardiovascular events, and change from baseline in the 6-minute walk test distance over 12 months. The third secondary end point was a composite of death from any cause, hospitalizations for any cause, and urgent heart failure visits over 12 months. RESULTS: A total of 360 patients were randomly assigned to receive patisiran (181 patients) or placebo (179 patients). At month 12, the decline in the 6-minute walk distance was lower in the patisiran group than in the placebo group (Hodges-Lehmann estimate of median difference, 14.69 m; 95% confidence interval [CI], 0.69 to 28.69; P = 0.02); the KCCQ-OS score increased in the patisiran group and declined in the placebo group (least-squares mean difference, 3.7 points; 95% CI, 0.2 to 7.2; P = 0.04). Significant benefits were not observed for the second secondary end point. Infusion-related reactions, arthralgia, and muscle spasms occurred more often among patients in the patisiran group than among those in the placebo group. CONCLUSIONS: In this trial, administration of patisiran over a period of 12 months resulted in preserved functional capacity in patients with ATTR cardiac amyloidosis. (Funded by Alnylam Pharmaceuticals; APOLLO-B ClinicalTrials.gov number, NCT03997383.).

World Heart Federation Consensus on Transthyretin Amyloidosis Cardiomyopathy (ATTR-CM).

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive and fatal condition that requires early diagnosis, management, and specific treatment. The availability of new disease-modifying therapies has made successful treatment a reality. Transthyretin amyloid cardiomyopathy can be either age-related (wild-type form) or caused by mutations in the TTR gene (genetic, hereditary forms). It is a systemic disease, and while the genetic forms may exhibit a variety of symptoms, a predominant cardiac phenotype is often present. This document aims to provide an overview of ATTR-CM amyloidosis focusing on cardiac involvement, which is the most critical factor for prognosis. It will discuss the available tools for early diagnosis and patient management, given that specific treatments are more effective in the early stages of the disease, and will highlight the importance of a multidisciplinary approach and of specialized amyloidosis centres. To accomplish these goals, the World Heart Federation assembled a panel of 18 expert clinicians specialized in TTR amyloidosis from 13 countries, along with a representative from the Amyloidosis Alliance, a patient advocacy group. This document is based on a review of published literature, expert opinions, registries data, patients' perspectives, treatment options, and ongoing developments, as well as the progress made possible via the existence of centres of excellence. From the patients' perspective, increasing disease awareness is crucial to achieving an early and accurate diagnosis. Patients also seek to receive care at specialized amyloidosis centres and be fully informed about their treatment and prognosis.

Changes in amyloidosis phenotype over 11 years in a cardiac amyloidosis referral centre cohort in France.

BACKGROUND: Early cardiac amyloidosis (CA) diagnosis enables patients to access effective treatments for better long-term outcomes, yet it remains under-recognised, misdiagnosed and inadequately managed. AIM: To reduce diagnostic delays, we aimed to describe the epidemiological and clinical characteristics and changes over an 11-year period. METHODS: This was a retrospective, observational cohort study of all patients referred to the Henri-Mondor Hospital for suspected CA. RESULTS: Overall, 3194 patients were identified and 3022 were included and analysed. Our patients came from varied ethnic backgrounds, and more than half (55.2%) had confirmed CA. Over 11 years, referrals increased 4.4-fold, mostly from cardiologists. Notably, wild-type transthyretin amyloidosis (ATTRwt) became the predominant diagnosis, with referrals increasing 15-fold from 20 in 2010-2012 to 308 in 2019-2020. The number of amyloid light chain (AL) diagnoses increased, whilst variant transthyretin amyloidosis (ATTRv) numbers remained relatively stable. Concerning disease severity, AL patients presented more frequently with severe cardiac involvement whereas an increasing number of ATTRwt patients presented with National Amyloid Centre stage I (22.0% in 2013-2014 to 45.9% in 2019-2020). Lastly, among patients diagnosed with ATTRv in 2019-2020, 83.9% had ATTR Val122Ile cardiac phenotype. CONCLUSIONS: This study shows that increasing cardiologist awareness and referrals have increased CA diagnoses. With improved awareness and non-invasive diagnostic techniques, more patients with ATTRwt with milder disease and more ATTRv Val122Ile mutations are being referred and diagnosed. Although more AL cases are being recognised, patients are diagnosed with severe cardiac involvement.

Prognostic value of soluble ST2 in AL and TTR cardiac amyloidosis: a multicenter study.

Background: Both light-chain (AL) amyloidosis and transthyretin (ATTR) amyloidosis are types of cardiac amyloidosis (CA) that require accurate prognostic stratification to plan therapeutic strategies and follow-ups. Cardiac biomarkers, e.g., N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (Hs-cTnT), remain the cornerstone of the prognostic assessment. An increased level of soluble suppression of tumorigenesis-2 (sST2) is predictive of adverse events [all-cause death and heart failure (HF) hospitalizations] in patients with HF. This study aimed to evaluate the prognostic value of circulating sST2 levels in AL-CA and ATTR-CA. Methods: We carried out a multicenter study including 133 patients with AL-CA and 152 patients with ATTR-CA. During an elective outpatient visit for the diagnosis of CA, Mayo Clinic staging [NT-proBNP, Hs-cTnT, differential of free light chains (DFLCs)] and sST2 were assessed for all AL patients. Gillmore staging [including estimated glomerular filtration rate (eGFR), NT-proBNP] and Grogan staging (including NT-proBNP and Hs-cTnT) were assessed for TTR-CA patients. Results: The median age was 73 years [interquartile range (IQR) 61-81], and 53% were men. The endpoint was the composite of all-cause death or first HF-related hospitalization. The median follow-up was 20 months (IQR 3-34) in AL amyloidosis and 33 months (6-45) in TTR amyloidosis. The primary outcome occurred in 70 (53%) and 99 (65%) of AL and TTR patients, respectively. sST2 levels were higher in patients with AL-CA than in patients with ATTR-CA: 39 ng/L (26-80) vs. 32 ng/L (21-46), p < 0.001. In AL-CA, sST2 levels predicted the outcome regardless of the Mayo Clinic score (HR: 2.16, 95% CI: 1.17-3.99, p < 0.001). In TTR-CA, sST2 was not predictive of the outcome in multivariate models, including Gillmore staging and Grogan staging (HR: 1.17, CI: 95% 0.77-1.89, p = 0.55). Conclusion: sST2 level is a relevant predictor of death and HF hospitalization in AL cardiac amyloidosis and adds prognostic stratification on top of NT-proBNP, Hs cTnT, and DFLC.

Comparison of cardiac involvement, extracardiac manifestations and outcomes between homozygote and heterozygote transthyretin p.Val142Ile (V122I) variant in patients with hereditary transthyretin amyloidosis: a cohort study.

BACKGROUND: Hereditary transthyretin (ATTRv) p.Val142Ile (V122I) mutation is the most common inherited cause of cardiac amyloidosis and little is known about the phenotype and outcome of the rare homozygotic genotype. This study aimed to compare phenotypic characteristics and outcomes between heterozygous and homozygous patients with ATTRv V122I amyloidosis. MATERIAL AND METHODS: This monocentric, observational, retrospective study conducted at the French National Referral Centre for Cardiac Amyloidosis (Henri Mondor Hospital, Créteil), described clinical, electrocardiographic, cardiac imaging features and prognostic data for patients with ATTRv V122I amyloidosis. RESULTS: Among 185 ATTRv V122I patients identified, 161 were heterozygous and 24 were homozygous. The homozygous frequency was 13%. Onset occured significantly earlier in the homozygotes compared to heterozygotes with earlier median age at diagnosis (67[63-71] years vs 76[70-79] years, p < .001), age at first cardiac symptom (66[61-71] years vs 74[68-78] years, p < .001) and age at first extracardiac symptom (59[52-70] years vs 69[62-75] years, p = .003). Homozygous ATTRv V122I was also associated with greater disease burden with earlier events (death, transplant or hospitalisation for acute heart failure) compared with heterozygotes (71[67-74] vs 78[76-79] years, p = .018). CONCLUSION: This rare, homozygous V122I cohort confirmed the earlier age of onset, death and cardiac events in this population.

Deep Learning on Bone Scintigraphy to Detect Abnormal Cardiac Uptake at Risk of Cardiac Amyloidosis.

BACKGROUND: Cardiac uptake on technetium-99m whole-body scintigraphy (WBS) is almost pathognomonic of transthyretin cardiac amyloidosis. The rare false positives are often related to light-chain cardiac amyloidosis. However, this scintigraphic feature remains largely unknown, leading to misdiagnosis despite characteristic images. A retrospective review of all WBSs in a hospital database to detect those with cardiac uptake may allow the identification of undiagnosed patients. OBJECTIVES: The authors sought to develop and validate a deep learning-based model that automatically detects significant cardiac uptake (Perugini grade ≥2) on WBS from large hospital databases in order to retrieve patients at risk of cardiac amyloidosis. METHODS: The model is based on a convolutional neural network with image-level labels. The performance evaluation was performed with C-statistics using a 5-fold cross-validation scheme stratified so that the proportion of positive and negative WBSs remained constant across folds and using an external validation data set. RESULTS: The training data set consisted of 3,048 images: 281 positives (Perugini grade ≥2) and 2,767 negatives. The external validation data set consisted of 1,633 images: 102 positives and 1,531 negatives. The performance of the 5-fold cross-validation and external validation was as follows: 98.9% (± 1.0) and 96.1% for sensitivity, 99.5% (± 0.4) and 99.5% for specificity, and 0.999 (SD = 0.000) and 0.999 for the area under the curve of the receiver-operating characteristic curves. Sex, age <90 years, body mass index, injection-acquisition delay, radionuclides, and the indication of WBS only slightly affected performances. CONCLUSIONS: The authors' detection model is effective at identifying patients with cardiac uptake Perugini grade ≥2 on WBS and may help in the diagnosis of patients with cardiac amyloidosis.

Phase 1 Trial of Antibody NI006 for Depletion of Cardiac Transthyretin Amyloid.

BACKGROUND: Transthyretin amyloid (ATTR) cardiomyopathy is a progressive and fatal disease caused by misfolded transthyretin. Despite advances in slowing disease progression, there is no available treatment that depletes ATTR from the heart for the amelioration of cardiac dysfunction. NI006 is a recombinant human anti-ATTR antibody that was developed for the removal of ATTR by phagocytic immune cells. METHODS: In this phase 1, double-blind trial, we randomly assigned (in a 2:1 ratio) 40 patients with wild-type or variant ATTR cardiomyopathy and chronic heart failure to receive intravenous infusions of either NI006 or placebo every 4 weeks for 4 months. Patients were sequentially enrolled in six cohorts that received ascending doses (ranging from 0.3 to 60 mg per kilogram of body weight). After four infusions, patients were enrolled in an open-label extension phase in which they received eight infusions of NI006 with stepwise increases in the dose. The safety and pharmacokinetic profiles of NI006 were assessed, and cardiac imaging studies were performed. RESULTS: The use of NI006 was associated with no apparent drug-related serious adverse events. The pharmacokinetic profile of NI006 was consistent with that of an IgG antibody, and no antidrug antibodies were detected. At doses of at least 10 mg per kilogram, cardiac tracer uptake on scintigraphy and extracellular volume on cardiac magnetic resonance imaging, both of which are imaging-based surrogate markers of cardiac amyloid load, appeared to be reduced over a period of 12 months. The median N-terminal pro-B-type natriuretic peptide and troponin T levels also seemed to be reduced. CONCLUSIONS: In this phase 1 trial of the recombinant human antibody NI006 for the treatment of patients with ATTR cardiomyopathy and heart failure, the use of NI006 was associated with no apparent drug-related serious adverse events. (Funded by Neurimmune; NI006-101 ClinicalTrials.gov number, NCT04360434.).

Patients with cardiac amyloidosis are at a greater risk of mortality and hospital readmission after acute heart failure.

AIMS: Cardiac amyloidosis (CA) is an under-diagnosed cause of heart failure (HF) and has a worse prognosis than other forms of HF. The frequency of death or rehospitalization following discharge for acute heart failure (AHF) in CA (relative to other causes) has not been documented. The study aims to compare hospital readmission and death rates 90 days after discharge for AHF in patients with vs. without CA and to identify risk factors associated with these events in each group. METHODS AND RESULTS: Patients with HF and CA (HF + CA+) were recruited from the ICREX cohort, after screening of their medical records. The cases were matched 1:5 by sex and age with control HF patients without CA (HF + CA-). There were 27 HF + CA + and 135 HF + CA- patients from the ICREX cohort included in the study. Relative to the HF + CA- group, HF + CA+ patients had a higher heart rate (P = 0.002) and N-terminal prohormone of brain natriuretic peptide levels (P < 0.001) and lower blood pressure (P < 0.001), weight, and body mass index values (P < 0.001) on discharge. Ninety days after discharge, the HF + CA+ group displayed a higher death rate, a higher all-cause hospital readmission rate, and a higher hospital readmission rate for AHF. Death and hospital readmissions occurred sooner after discharge in the HF + CA+ group than in the HF + CA- group. CONCLUSIONS: The presence of CA in patients with HF was associated with a three-fold greater risk of death and a two-fold greater risk of all-cause hospital readmission 90 days after discharge. These findings emphasize the importance of close, active management of patients with CA and AHF.

Amylo-AFFECT-QOL, a self-reported questionnaire to assess health-related quality of life and to determine the prognosis in cardiac amyloidosis.

Background and aims: Self-reported questionnaires are useful for estimating the health-related quality of life (HR-QoL), impact of interventions, and prognosis. To our knowledge, no HR-QoL questionnaire has been developed for cardiac amyloidosis (CA). This study aimed to validate Amylo-AFFECT-QOL questionnaire to assess HR-QoL and its prognostic value in CA. Methods: A self-reported questionnaire, "Amylo-AFFECT" had been designed and validated for CA symptoms evaluation and screening by physicians. It was adapted here to assess HR-QoL (Amylo-AFFECT-QOL) and its prognostic value in CA. To validate the theoretical model, internal consistency and convergent validity were assessed, particularly correlations between Amylo-AFFECT-QOL and the HR-QoL Minnesota Living Heart Failure (MLHF) questionnaire. Results: Amylo-AFFECT-QOL was completed by 515 patients, 425 of whom (82.5%) had CA. Wild-type and hereditary transthyretin amyloidosis (ATTRwt and ATTRv) and immunoglobulin light-chain amyloidosis (AL) were diagnosed in 47.8, 14.7, and 18.8% of cases, respectively. The best HR-QoL evaluation was obtained with five dimensions: "Heart failure," "Vascular dysautonomia," "Neuropathy," "Ear, gastrointestinal, and urinary dysautonomia," and "Skin or mucosal involvement." The global Amylo-AFFECT-QOL and MLHF scores showed significant positive correlations (rs = 0.72, p < 0.05). Patients with a final diagnosis of CA had a global Amylo-AFFECT-QOL score significantly higher than the control group composed by patients with other diagnoses (22.2 ± 13.6 vs. 16.2 ± 13.8, respectively, p-value < 0.01). According to the Amylo-AFFECT-QOL global results, ATTRv patients' QoL was more affected than AL patients' QoL or ATTRwt patients' QoL. Patients with a higher HR-QoL score had a greater risk of death or heart transplant after 1 year of follow-up (log-rank < 0.01). Conclusion: Amylo-AFFECT-QOL demonstrates good psychometric properties and is useful for quantifying HR-QoL and estimating CA prognosis. Its use may help to improve overall management of patients with CA.

3D-Printed, Liquid-Filled Capsules of Concentrated and Stabilized Polyphenol Epigallocatechin Gallate, Developed in a Clinical Trial.

In vitro studies have shown that epigallocatechin gallate (EGCG), the most potent antioxidant of the green tea polyphenol catechins, is able to effectively prevent the formation of amyloid plaques and induce their clearance. However, its high chemical reactivity promotes high chemical instability, which represents a major obstacle for the development of pharmaceutical forms containing solubilized EGCG, an essential condition for a better systemic passage via the oral route. After discovering that EGCG forms a deep eutectic with choline chloride, we exploited this property to formulate and patent liquid-filled capsules containing 200-800 mg of soluble EGCG in easy-to-administer sizes. The gelatin envelopes used are of the conventional type and their filling has been achieved using 3D printing technology. Not only did the EGCG-choline complex allow the formulation of hydrophilic solutions with a high concentration of active substance but it also contributed significantly to its chemical stability, since after at least 18 months of storage at 25 °C/60% RH and one year at 40 °C/75% RH, the capsules show unchanged hardness, chromatographic profiles and antioxidant activity compared to T0. Preclinical studies in monkeys showed that bioavailability was increased by a factor of 10 compared to marketed capsules comprising EGCG powder. This pharmaceutical development was conducted in the context of upcoming clinical trials to evaluate EGCG alone or in combination when treating transthyretin and light-chain cardiac amyloidosis.

Pathological spectrum of hereditary transthyretin renal amyloidosis and clinicopathologic correlation: a French observational study.

BACKGROUND: Cardiac and neurological involvements are the main clinical features of hereditary transthyretin (ATTRv) amyloidosis. Few data are available about ATTRv amyloid nephropathy (ATTRvN). METHODS: We retrospectively included 30 patients with biopsy-proven ATTRvN [V30M (26/30) including two domino liver recipients, S77Y (2/30), V122I (1/30) and S50R (1/30) variants] from two French reference centers. We described the pathological features by comparing amyloid deposits distribution to patients with AL or AA amyloidosis, and sought to determine clinicopathological correlation with known disease-modifying factors such as TTR variant, gender and age at diagnosis. RESULTS: In comparison with AL and AA amyloidosis, ATTRv patients had similar glomerular, arteriolar and arterial amyloid deposits, but more cortical and medullary tubulointerstitial (33%, 44%, 77%, P = .03) involvement. While the presence of glomerular deposits is associated with the range of proteinuria, some patients with abundant glomerular ATTRv amyloidosis had no significant proteinuria. V30M patients had more glomerular (100% and 25%, odds ratio = 114, 95% confidence interval 3.85-3395.00, P = .001) deposits, and higher estimated glomerular filtration rate [50 (interquartile range 44-82) and 27 (interquartile range 6-31) mL/min/1.73 m², P = .004] than non-V30M patients. We did not find difference in amyloid deposition according to gender or age at diagnosis. CONCLUSION: ATTRvN affects all kidney compartments, but compared with AL/AA amyloidosis, ATTRvN seems to involve more frequently tubulointerstitial areas. V30M patients represents the dominant face of the disease with a higher risk of glomerular/arteriolar involvement. ATTRvN should thus be considered in patients, and potential relatives, with ATTRv amyloidosis and kidney dysfunction, regardless of proteinuria level.

Natural course and determinants of short-term kidney function decline in hereditary transthyretin amyloidosis: a French observational study.

Data regarding renal involvement in patients with hereditary transthyretin (ATTRv) amyloidosis are scarce and the natural course of chronic kidney disease (CKD) in this population remains unclear. This observational study, including adult patients diagnosed with ATTRv amyloidosis at the French Reference Centre for Cardiac Amyloidosis, investigated renal function outcome and its determinants. Multivariable logistic regression models identified factors associated with CKD at baseline. Determinants of the change in estimated glomerular filtration rate (eGFR) over 24 months of follow-up were assessed with a multivariable linear mixed-effects model. In total, 232 patients (78 women [34%], mean age: 64 years) with ATTRv amyloidosis were classified on the basis of their TTR variants: ATTRV122I (37%), ATTRV30M (29%), and other variants (34%). Median baseline eGFR was 78 ml/min/1.73 m2. Seventy-two patients (31%) had an eGFR below 60 ml/min/1.73m2 and 27/137 patients (20%) had significant proteinuria (urine protein/creatinine ratio ≥30 mg/mmol). Renal biopsy, performed in four cases, found typical Congo red-positive and TTR-labelled amyloid deposits in all cases. Older age (OR 1.07, p < .001) and a prior history of hypertension (OR 2.09, p = .04) were associated with a higher prevalence of CKD at baseline, whereas higher left ventricular global longitudinal strain (LVGLS) (OR 0.83, p < .001) was associated with a lower prevalence. The estimated change in eGFR was -7.12 [-9.61, -4.63] and -8.21 [-10.81, -5.60] ml/min/1.73 m2 after 12 and 24 months of follow-up, respectively. eGFR decline was independently associated with older age ((67-74], coefficient= -14.35 mL/min/1.73 m2, p < .01, >74, coefficient = -22.93 mL/min/1.73 m2, p < .001, versus <56), ATTRV122I (coefficient = -17.17 mL/min/1.73m2, p < .01, versus ATTRV30M) and LVGLS (coefficient = 1.22, p < .01). These data suggest that CKD is a common finding in patients with ATTRv amyloidosis, and that eGFR decline is rapid during the first year of evaluation. Older age, lower LVGLS and ATTRV122I were associated with a worse renal outcome. Further studies are now needed to evaluate effects of new targeted therapies on long term renal function.