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Aims: Disease staging and prognostic scoring in wild-type transthyretin-related cardiac amyloidosis (ATTRwt-CA) can be captured by two systems (NAC and Columbia scores). However, uncertainty remains as epidemiology of the disease is evolving rapidly. We evaluated features associated with staging systems across ATTRwt-CA patients from different diagnostic pathways, and their association with prognosis., Methods: We performed an analysis on DIAMOND patients with available data to evaluate NAC and Columbia score. DIAMOND was a retrospective study from 17 Italian referral centres for CA, enrolling 1281 patients diagnosed between 2016 and 2021, and aimed at describing characteristics of pathways leading to ATTRwt-CA diagnosis. Of the original cohort, 811 patients were included in this analysis. Each patient had NAC and Columbia score calculated. Patients were grouped according to NAC and Columbia scoring classes. We described characteristics of patients according to staging classes and diagnostic pathways at diagnosis. Prevalence of early diagnoses, defined as NAC Ia, NYHA class I, no use of diuretics, no history of heart failure (HF) hospitalizations nor of atrial fibrillation prior to diagnosis, was investigated. Finally, prognostic variables were tested alone and grouped as NAC or Columbia scores in Cox univariate and multivariate regression analyses. Prognosis was investigated as all-cause mortality, in the whole population and dividing patients in HF versus other diagnostic pathways., Results: Only 1% of the study population had an early ATTRwt-CA diagnosis. Distribution of prognostic variables and of NAC and Columbia classes was heterogeneous across diagnostic pathways. The prevalence of NAC III and Columbia III was higher in the HF diagnostic pathway, but all NAC and Columbia classes were present in all pathways. Both NAC and Columbia scores were associated with all-cause mortality at univariate Cox regression analysis in the whole population, in patients from the HF diagnostic pathway and in those from other pathways. At multivariate analysis, Columbia score remained significantly associated with the outcome, together with age at diagnosis, left ventricular ejection fraction and maximal wall thickness., Conclusions: In this contemporary nationwide cohort, an ATTRwt-CA early diagnosis was very rare. Disease staging with NAC and Columbia scoring systems determined classes of patients with heterogeneous features. Both scores were significantly associated with mortality, but other variables also had prognostic significance., (© 2024 The Author(s). ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: The introduction of a noninvasive diagnostic algorithm in 2016 led to increased awareness and recognition of cardiac amyloidosis (CA)., Objectives: The purpose of this study was to analyze the impact of the introduction of the noninvasive diagnostic algorithm on diagnosis and prognosis in a multicenter Italian CA cohort., Methods: This was a retrospective analysis of 887 CA patients from 5 Italian Cardiomyopathies Referral Centers: 311 light-chain CA, 87 variant transthyretin (TTR)-related CA, 489 wild-type TTR-related CA. Clinical characteristics and outcomes (all-cause mortality and heart failure [HF] hospitalizations) were compared overall and for each CA subtype between patients diagnosed before versus after 2016. Outcomes were further compared by propensity score weighted Kaplan-Meier analysis and Cox regression analysis., Results: CA diagnoses increased after 2016, in particular for wild-type TTR-related CA. Patients diagnosed after versus before 2016 were older, had less frequently a history of HF prior to diagnosis, and NYHA functional class III-IV at diagnosis. Over a median follow-up of 18 months, 172 (86%) patients diagnosed before 2016 died or had an HF hospitalization, versus 300 (44%) diagnosed after 2016. Propensity score weighted Kaplan-Meier analysis showed worse outcomes ( P  < 0.001) for patients diagnosed before 2016. At Cox regression analysis, CA diagnosis after 2016 was an independent protective factor for the composite outcome (HR: 0.69; P  = 0.001), with interaction by CA subtype (significant in TTR-related CA and null in light-chain)., Conclusions: CA patients diagnosed after 2016 showed a less severe phenotype and a better prognosis. The impact of the noninvasive diagnostic algorithm on outcomes was particularly relevant in TTR-related CA., Competing Interests: The work reported in this publication was funded by the 10.13039/501100003196Italian Ministry of Health, RC-2022-2773270 project. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Transthyretin cardiac amyloidosis (ATTR-CA) predominantly affects older adults with multiple chronic conditions, leading to significant physical, cognitive, and emotional challenges. New disease-modifying drugs are effective in early stages, prompting a shift toward comprehensive assessments, including functional capacity and quality of life. However, these assessments may not fully capture the complexity of older ATTR-CA patients, especially regarding frailty and mood disorders, which can influence symptom reporting. Thus, integrating comprehensive geriatric assessment tools into routine clinical practice may be crucial to detect early signs of frailty or functional impairment that could impact outcomes and mitigate futility and ageism in the decision-making process. This review highlights the importance of evaluating multimorbidity, disability, and frailty in older patients with ATTR-CA to optimize management strategies., Competing Interests: Dr Maurer is supported by grant from 10.13039/100000002NIH R01HL139671 and R01AG081582-01; grants and personal fees from Alnylam, Pfizer, Eidos, Prothena, and Ionis; and personal fees from AstraZeneca, Akcea, Intellia, and Novo Nordisk. Dr Fontana is supported by a British Heart Foundation Intermediate Clinical Research Fellowship (FS/18/21/33447). Dr Gillmore has received consultancy fees from Alnylam, AstraZeneca, ATTRalus, Bridgebio, Ionis, Intellia, Lycia, and Pfizer. Dr Goyal is supported by 10.13039/100000049National Institute on Aging grants K76AG064428, R21AG077092, R01AG085420, and R24AG064025; and has received consulting fees from Agepha Pharma, Akros Pharma, Axon therapies, and Sensorum Health. Dr Fine has received research support and consulting honoraria from Pfizer, Alnylam, Ionis, AstraZeneca, Novo Nordisk, Sanofi/Genzyme, and Eidos/BridgeBio. Dr Grogan has received research support and or advisory board/consulting fees from Alnylam, BridgeBio/Eidos, Janssen, Pfizer, AstraZeneca, Novo, and Nordisk (all funds paid to employer, no personal compensation). Dr Marfella is supported by Programmi di Ricerca Scientifica di Rilevante Interesse Nazionale (Scientific research programs of high national interest) # 2020LM8WNW. Dr Limongelli has received research support and or advisory board/consulting fees from Alnylam, Pfizer, and AstraZeneca. Dr Longhi is supported by the Italian Ministry of Health, RC-2022-2773270 project. Dr Cuddy is supported by grant support from 10.13039/100000002NIH 1K23HL166686-01 and 10.13039/100000967AHA 23CDA857664; and has received personal fees from Pfizer, Bridgebio, Ionis, AstraZeneca, and Novo Nordisk. Dr Masri is supported by Research Grants from 10.13039/100004319Pfizer, Ionis, Attralus, and 10.13039/100014941Cytokinetics; and has received fees from Cytokinetics, BMS, Eidos, Pfizer, Ionis, Lexicon, Attralus, Haya, BioMarin, Alexion, and Tenaya. Dr Olivotto is supported by grants for “Respect,” “StratifyHF,” and “SmashHCM” and has received grants from 10.13039/100015340Bayer, 10.13039/100016619MyoKardia, Inc, which is a wholly owned subsidiary of Bristol Myers Squibb, Sanofi Genzyme, and Shire, which is now part of Takeda; personal fees from Bayer, Sanofi Genzyme, and Shire/Takeda; and payments as a consultant from MyoKardia, Inc. Dr Perfetto has received honoraria for advisory board participation from Pfizer, Alnylam, and Akcea. Dr Ungar is supported by Piano Nazionale di Ripresa e Resilienza grants. Dr Cappelli has received consultant fees from Pfizer, Alnylam, AstraZeneca, BridgeBio, Daiichi Sankyo, and Novo Nordisk. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Background: Amyloid deposition in tenosynovial structures precedes cardiac involvement up to 20 years. Therefore, a cardiological screening in patients with a history of tenosynovial manifestations of cardiac amyloidosis (CA) could lead to an increased number of early diagnoses., Methods: Patients with tenosynovial manifestations of CA (carpal tunnel syndrome, atraumatic biceps tendon rupture, lumbar spinal stenosis) have been identified by general practitioners and evaluated in a Referral Center for CA. Patients with a high suspicion of CA underwent the CA diagnostic pathway., Results: Among 50 General Practitioners (GP) contacted, 10 (20%) agreed to participate in the study for a total of 5615 patients ≥60 years. One hundred forty-five patients met the inclusion criteria, 2 of them already had a diagnosis of CA, and 57 agreed to undergo a cardiological evaluation (electrocardiography, echocardiography, NTproBNP assay). The median age was 73 [67-80] years and 31 (54%) were women. Eight patients were suggested to start the CA diagnostic pathway, five of them underwent a complete diagnostic evaluation for CA, three refused to complete the diagnostic exams and no new diagnoses were made., Conclusion: A screening program for CA in patients with tenosynovial manifestations identified by general practitioners is feasible, but may not yield a high rate of new diagnosis. In this study, we identified two patients who already had a diagnosis of CA, and among patients at high risk for CA, 37% refused to complete the diagnostic pathway. Increased awareness of CA among patients might increase participation and diagnostic yield in screening studies. Further validation of this protocol is needed to evaluate its diagnostic performance., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

Background: Atrial fibrillation (AF) is common in patients with cardiac amyloidosis (CA) and is a significant risk factor for heart failure hospitalization and thromboembolic events., Objective: This study was designed to investigate the atrial electrofunctional predictors of incident AF in CA., Methods: A multicenter, observational study was conducted in 4 CA referral centers including sinus rhythm patients with light-chain (AL) and transthyretin (ATTR) CA undergoing electrocardiography and cardiac magnetic resonance imaging. The primary end point was new-onset AF occurrence., Results: Overall, 96 patients (AL-CA, n = 40; ATTR-CA, n = 56) were enrolled. During an 18-month median follow-up (Q1-Q3, 7-29 months), 30 patients (29%) had incident AF. Compared with those without AF, patients with AF were older (79 vs 73 years; P = .001). They more frequently had ATTR (87% vs 45%; P < .001); electrocardiographic interatrial block (IAB), either partial (47% vs 21%; P = .011) or advanced (17% vs 3%; P = .017); and lower left atrial ejection fraction (LAEF; 29% vs 41%; P = .004). Age (hazard ratio [HR], 1.059; 95% CI, 1.002-1.118; P = .042), any type of IAB (HR, 2.211; 95% CI, 1.03-4.75; P = .041), and LAEF (HR, 0.967; 95% CI, 0.936-0.998; P = .044) emerged as independent predictors of incident AF. Patients exhibiting any type of IAB, LAEF <40%, and age >78 years showed a cumulative incidence for AF of 40% at 12 months. This risk was significantly higher than that carried by 1 (8.5%) or none (7.6%) of these 3 risk factors., Conclusion: In patients with CA, older age, IAB on 12-lead electrocardiography, and reduced LAEF on cardiac magnetic resonance imaging are significant and independent predictors of incident AF. A closer screening for AF is advisable in CA patients carrying these features., Competing Interests: Disclosures A.C. received honoraria from Alnylam, AstraZeneca, and Pfizer., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Cardiac amyloidosis (CA) is an infiltrative cardiomyopathy divided into two types: light-chain (LA) and transthyretin (ATTR) CA. Cardiac magnetic resonance (CMR) has emerged as an important diagnostic tool in CA. While late gadolinium enhancement (LGE), T1 mapping and extracellular volume (ECV) have a consolidate role in the assessment of CA, T2 mapping has been less often evaluated. We aimed to test the value of T2 mapping in the evaluation of CA. This study recruited 70 patients with CA (51 ATTR, 19 AL). All the subjects underwent 1.5 T CMR with T1 and T2 mapping and cine and LGE imaging. Their QALE scores were evaluated. The myocardial T2 values were significantly ( p < 0.001) increased in both types of CA compared to the controls. In the AL-CA group, increased T2 values were associated with a higher QALE score. The myocardial native T1 values and ECV were significantly ( p < 0.001) higher in the CA patients than in the healthy subjects. Left ventricular (LV) mass, QALE score and ECV were higher in ATTR amyloidosis compared with AL amyloidosis, while the LV ejection fraction was lower ( p < 0.001). These results support the concept of the presence of myocardial edema in CA. Therefore, a CMR evaluation including not only myocardial T1 imaging but also myocardial T2 imaging allows for more comprehensive tissue characterization in CA.

Background: Whether, and to what extent, frailty and other geriatric domains are linked to health status in patients with transthyretin cardiac amyloidosis (ATTR-CA) is unknown., Aims: To determine the association of frailty with health status [defined by the Kansas City Cardiomyopathy Questionnaire (KCCQ)] in patients with ATTR-CA., Methods: Consecutive ATTR-CA patients undergoing cardiovascular assessment at a tertiary care clinic from September 2021 to September 2023 were invited to participate. KCCQ, frailty and social environment were recorded. Frailty was assessed using the modified Frailty Index (mFI), mapping 11 variables from the Canadian Study of Health and Aging (frailty ≥0.36)., Results: Of 168 screened ATTR-CA patients, 138 [83% men, median age of 79 (75-84) years] were enrolled in the study. Median KCCQ was 66 (50-75). wtATTR-CA was the most prevalent form (N = 113, 81.9%). The most frequent cardiac variant was Ile68Leu (17/25 individuals with vATTR-CA). Twenty (14.5%) patients were considered frail, and prevalence of overt disability was 6.5%. At multivariable linear regression analysis, factors associated with worsening KCCQ were age at evaluation, the mFI, NYHA Class, and NAC Score. Gender, ATTR-CA type, phenotype, and LVEF were not associated with health status., Discussion: In older patients diagnosed with ATTR-CA, frailty, symptoms, and disease severity were associated with KCCQ., Conclusions: Functional status is a determinant of quality of life and health status in older individuals with a main diagnosis of ATTR-CA. Future research may provide more in-depth knowledge on the association of frailty in patients with ATTR-CA with respect to quality of life and prognosis., (© 2024. The Author(s).)

Background: The extent of myocardial bone tracer uptake with technetium pyrophosphate, hydroxymethylene diphosphonate, and 3,3-diphosphono-1,2-propanodicarboxylate in transthyretin amyloid cardiomyopathy (ATTR-CM) might reflect cardiac amyloid burden and be associated with outcome., Methods: Consecutive patients with ATTR-CM who underwent diagnostic bone tracer scintigraphy with acquisition of whole-body planar and cardiac single-photon emission computed tomography (SPECT) images from the National Amyloidosis Centre and 4 Italian centers were included. Cardiac uptake was defined according to the Perugini classification: 0=absent cardiac uptake; 1=mild uptake less than bone; 2=moderate uptake equal to bone; and 3=high uptake greater than bone. Extent of right ventricular (RV) uptake was defined as focal (basal segment of the RV free wall only) or diffuse (extending beyond basal segment) on the basis of SPECT imaging. The primary outcome was all-cause mortality., Results: Among 1422 patients with ATTR-CM, RV uptake accompanying left ventricular uptake was identified by SPECT imaging in 100% of cases at diagnosis. Median follow-up in the whole cohort was 34 months (interquartile range, 21 to 50 months), and 494 patients died. By Kaplan-Meier analysis, diffuse RV uptake on SPECT imaging (n=936) was associated with higher all-cause mortality compared with focal (n=486) RV uptake (77.9% versus 22.1%; P <0.001), whereas Perugini grade was not associated with survival ( P =0.27 in grade 2 versus grade 3). On multivariable analysis, after adjustment for age at diagnosis (hazard ratio [HR], 1.03 [95% CI, 1.02-1.04]; P <0.001), presence of the p.(V142I) TTR variant (HR, 1.42 [95% CI, 1.20-1.81]; P =0.004), National Amyloidosis Centre stage (each category, P <0.001), stroke volume index (HR, 0.99 [95% CI, 0.97-0.99]; P =0.043), E/e' (HR, 1.02 [95% CI, 1.007-1.03]; P =0.004), right atrial area index (HR, 1.05 [95% CI, 1.02-1.08]; P =0.001), and left ventricular global longitudinal strain (HR, 1.06 [95% CI, 1.03-1.09]; P <0.001), diffuse RV uptake on SPECT imaging (HR, 1.60 [95% CI, 1.26-2.04]; P <0.001) remained an independent predictor of all-cause mortality. The prognostic value of diffuse RV uptake was maintained across each National Amyloidosis Centre stage and in both wild-type and hereditary ATTR-CM ( P <0.001 and P =0.02, respectively)., Conclusions: Diffuse RV uptake of bone tracer on SPECT imaging is associated with poor outcomes in patients with ATTR-CM and is an independent prognostic marker at diagnosis., Competing Interests: Disclosures The authors report no conflicts in relation to the submitted work. They report the following conflicts outside the submitted work: Dr Rapezzi served on the Italian scientific advisory board of Pfizer and received unrestricted research grants and personal fees from Pfizer and personal fees from Alnylam Pharmaceuticals. Dr Biagini received advisory board fees from Sanofi, Genzyme, and Takeda. Dr Cappelli received advisory board fees from Pfizer and Akcea and research grants from Pfizer. Dr Sinagra received personal fees for occasional educational activities from Biotronik, Boston Scientific, AstraZeneca, and Novartis. Dr Canepa received speaker and advisor fees from Akcea Therapeutics, Menarini, Novartis, Pfizer, Sanofi e Sanofi Genzyme, and Vifor Pharma, as well as 2 investigator-initiated grants from Pfizer. Dr Fontana is supported by a British Heart Foundation intermediate clinical research fellowship (FS/18/21/33447). Dr Merlo received congress fees from Novartis and Vifor Pharma and research grant and congress fees from Pfizer. Dr Gillmore receives advisory board fees from Pfizer, Alnylam, ATTRalus, Intellia, AstraZeneca, and BridgeBio.

Background: Transthyretin amyloid cardiomyopathy (ATTR-CM) is associated with a progressive reduction of functional capacity. The progression of cardiopulmonary exercise testing (CPET) parameters over time is still unknown., Methods: In this study, 55 patients with ATTR-CM underwent 2 serial cardiologic evaluations and CPETs in a national referral center for cardiac amyloidosis (Careggi University Hospital, Florence)., Results: Forty-three patients (78%) had wild-type ATTR. Median age was 80 years (interquartile range [IQR] 76-83 years), and 50 of the patients (91%) were men. At baseline, median peak oxygen consumption (pVO 2 ) was 15 mL/kg/min (IQR 12-18 mL/kg/min), percentage of predicted pVO 2 (%ppVO 2 ) was 71% (IQR 60%-83%) and VE/VCO 2 slope was 31 (IQR 26-34). After a median follow-up of 14 months (IQR 13-16 months), pVO 2 , %ppVO 2 and VE/VCO 2 slope were significantly worsened (-1.29 mL/kg/min [95% confidence interval (CI): -1.85 to -0.74; P < 0.01], -4.5% [95% CI: -6.9 to -2.02; P < 0.01], and 8.6 [95% CI 6-11; P < 0.01], respectively). Furthermore, exercise time (-39 s, 95% CI: -59 to -19; P < 0.01), exercise tolerance (-0.47 metabolic equivalents, 95% CI: -0.69 to -0.2; P < 0.01), and peak systolic pressure (-10.8 mm Hg, 95% CI: -16.2 to -5.4; P < 0.01) were significantly reduced. The worsening in CPET variables did not correspond with a significant change in echocardiographic parameters., Conclusions: Cardiorespiratory response to exercise significantly worsened over a short period of time in patients with ATTR-CM. Serial CPET may be useful to identify early disease progression., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Transthyretin cardiac amyloidosis (ATTR-CA) has a deep impact on the quality of life (QoL), yet no specific patient-reported outcome measures (PROMs) for ATTR-CA exist., Methods: The ITALY study involved 5 Italian referral centres (Pisa, Pavia, Ferrara, Florence, Messina) enrolling consecutive outpatients with ATTR-CA., Results: Two 30-item questionnaires were created for wild-type (wt) and variant (v) ATTR-CA. Scores ranged from 100 (best condition) to 0 (worst condition). Out of 140 patients enrolled (77% with ATTRwt-CA), 115 repeated the re-evaluation at 6 months. At baseline, only 30% of patients needed help to fill out the questionnaires. Among baseline variables, all KCCQ and SF-36 domains were univariate predictors of ITALY scores in ATTRwt-CA patients, with the KCCQ Symptom Summary score (beta coefficient 0.759), Social Limitations (0.781), and Overall summary score (0.786) being the strongest predictors. The SF-36 Emotional well-being score (0.608), the KCCQ Overall summary score (0.656), and the SF-36 Energy/fatigue score (0.669) were the strongest univariate predictors of ITALY scores in ATTRv-CA. Similar results were found at 6 months., Conclusions: The ITALY questionnaires are the first specific PROMs for ATTRwt- and ATTRv-CA. Questionnaire completion is feasible. ITALY scores display close relationships with non-ATTR-specific measures of QoL.

Background: Tafamidis 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)., Objectives: This study was a post hoc analysis exploring tafamidis efficacy in octogenarian patients., Methods: Analysis 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., Results: After 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., Conclusions: The 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)., Competing Interests: Funding Support and Author Disclosures This study was sponsored by Pfizer. Pfizer contributed to the design and conduct of the study and management and collection of data. In their role as authors, employees of Pfizer were involved in the analysis and interpretation of data, preparation, review, and approval of the manuscript and the decision to submit for publication, along with their co-authors. The study sponsor approved the manuscript from an intellectual property perspective but had no right to veto the publication. Dr Garcia-Pavia has served as a speaker in scientific meetings for Alexion, Alnylam, BridgeBio, Ionis, AstraZeneca, Novo Nordisk, and Pfizer; has received funding from Alnylam and Pfizer for scientific meeting expenses; has received consultancy fees from Alnylam, Attralus, BridgeBio, Neuroimmune, AstraZeneca, Novo Nordisk, Alexion, Intellia, and Pfizer; and his institution has received research grants/educational support from Alnylam, AstraZeneca, BridgeBio, Intellia, and Pfizer. Dr Sultan and Mr Gundapaneni are full-time employees of Pfizer and hold stock/stock options. Dr Sekijima has a patent concerning tafamidis; has received honoraria for lectures and advisory board participation from Pfizer and Alnylam; and his institution has received research grants from Pfizer and Alnylam. Dr Perfetto has received honoraria for advisory board participation from Pfizer, Alnylam, and Akcea. Dr Hanna has received honoraria for advisory board participation from Pfizer, Alnylam, Akcea, Alexion, and Eidos; and has served as a speaker for a scientific meeting session funded by Alnylam. Dr Witteles has received honoraria for advisory board participation from Pfizer, Alnylam, Ionis, AstraZeneca, Janssen, Intellia, BridgeBio, Novo Nordisk, and Alexion., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Caregivers' psychological well-being is linked to the quality of care provided for familiar with chronic illness. Despite caregivers of cardiac patients present an impaired psychological well-being, less investigated is the psychological well-being of caregivers of individuals with a rare disease such as the Transthyretin Cardiac Amyloidosis (ATTR-CA). Specifically, given that no study explored the well-being of the caregiver and the caregiver-patient relationship, this study aimed to analyze the prevalence of anxiety and depression in ATTR-CA caregivers and if these disorders were associated with patient's and caregiver's characteristics. Fifty-eight dyad caregiver-ATTR-CA patients completed the Hospital Anxiety and Depression Scale and the Network of Relationships Inventory. Moreover, ATTR-CA patients completed the Kansas City Cardiomyopathy Questionnaire, while caregivers completed the Multidimensional Scale of Social Support. Results showed that anxious caregivers (44%) reported higher conflict with patients. They had ATTR-CA relatives with a worse perception of cardiac symptoms and higher anxiety and depression. Depressed caregivers (39%) reported higher conflict with ATTR-CA relatives and lower perceived social support. Caregiver reported a high prevalence of anxiety and depression associated with worse personal relational well-being and to patient's psycho-physical condition. The care of ATTR-CA patient should consider the caregiver well-being.

Backgorund: Hereditary transthyretin(vATTR) cardiac amyloidosis has extremely different features according to the type of transthyretin(TTR) mutation. Data about electrocardiographic findings(ECG) in vATTR are limited and not informative of genotype correlation. Aim of this study is to analyze ECG characteristics and their correlation to clinical and echocardiographic aspects in patients with vATTR, focusing on different TTR mutations., Methods and Results: This is a multicentric, retrospective, observational study performed in six Italian referral centres. We divided patients in two groups, according to the previously described phenotypic manifestations of the TTR mutation. Of 64 patients with vATTR, 23(36%) had prevalent cardiac(PC) TTR mutations and 41(64%) patients had a prevalent neurological(PN) TTR mutations. Patients with PC mutations were more frequently males and older, with advanced NAC staging. At baseline ECG, atrial fibrillation was more common in patients with PC, while pacemaker induced rhythm in PN mutations. PQ and QRS durations were longer and voltage to mass ratio was lower in PC mutations. Different TTR mutations tend to have distinctive ECG features., Conclusions: ECG in vATTR is extremely heterogeneous and the specific mutations are associated with distinct instrumental and clinical features. The differences between PN and PC vATTR are only partially explained by the different degree of cardiac infiltration., Competing Interests: Declaration of Competing Interest The authors report there are no competing interests to declare., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Data on the incidence and factors associated with de novo atrial fibrillation (AF) in patients with wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) is limited. We described the incidence and factors associated with de novo AF in patients diagnosed with ATTRwt-CA to drive tailored arrhythmia screening., Methods: Multicenter, retrospective, observational cohort study performed in six referral centers for CA. All consecutive patients diagnosed with ATTRwt-CA between 2004 and 2020 with >6-month follow up (FU) were enrolled and divided into three groups according to presence of AF: (1)patients with 'known AF'; (2)patients in 'sinus rhythm' and (3)patients developing 'de novo AF' during FU. Incidence and factors associated with AF in patients with ATTRwt were the primary outcomes., Results: Overall, 266 patients were followed for a median of 19 [11-33] months: 148 (56%) with known AF, 84 (31.6%) with sinus rhythm, and 34 (12.8%) with de novo AF. At Fine-Gray competing risk analysis to account for mortality, PR (sub-distribution hazard ratio [SHR] per Δms: 1.008, 95% C.I. 1.001-1.013, p = 0.008), QRS (SHR per Δms: 1.012, 95% C.I. 1.001-1.022, p = 0.046) and left atrial diameter ≥ 50 mm (SHR: 2.815,95% C.I. 1.483-5.342, p = 0.002) were associated with de novo AF. Patients with at least two risk factors (PR ≥ 200 ms, QRS ≥ 120 ms or LAD≥50 mm) had a higher risk of developing de novo AF compared to patients with no risk factors (HR 14.918 95% C.I. 3.242-31.646, p = 0.008)., Conclusions: At the end of the study almost 70% patients had AF. Longer PR and QRS duration and left atrial dilation are associated with arrhythmia onset., Competing Interests: Declaration of Competing Interest none to declare for the present work. All authors participated in the research and preparation of the manuscript., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Earth's atmosphere, whose ionization stability plays a fundamental role for the evolution and endurance of life, is exposed to the effect of cosmic explosions producing high energy Gamma-ray-bursts. Being able to abruptly increase the atmospheric ionization, they might deplete stratospheric ozone on a global scale. During the last decades, an average of more than one Gamma-ray-burst per day were recorded. Nevertheless, measurable effects on the ionosphere were rarely observed, in any case on its bottom-side (from about 60 km up to about 350 km of altitude). Here, we report evidence of an intense top-side (about 500 km) ionospheric perturbation induced by significant sudden ionospheric disturbance, and a large variation of the ionospheric electric field at 500 km, which are both correlated with the October 9, 2022 Gamma-ray-burst (GRB221009A)., (© 2023. The Author(s).)

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.)., (Copyright © 2023 Massachusetts Medical Society.)

The limited available data regarding the prevalence of transthyretin amyloidosis, both for wild-type (ATTRwt) and hereditary form (ATTRv), is inferred from highly selected patients and subsequent extrapolations that limit the comprehension of the clinical disease impact. The Tuscan healthcare system in 2006 developed a web-based rare disease registry, to monitor and profile patients affected by rare diseases. Clinicians belonging to regional validated healthcare data centres can register patients at the diagnosis, with a rigorous approach and distinguishing the types of amyloidosis, i.e., ATTRwt versus ATTRv. Thanks to this data collection method, available from July 2006 and extended with electronic therapy plans related to a diagnosis since May 2017, we analysed prevalence and incidence of ATTR and its subtypes. On November 30th 2022, ATTRwt prevalence in Tuscany is 90.3 per 1,000,000 persons and ATTRv prevalence is 9.5 per 1,000,000 persons, whereas the annual incidence ranges from 14.4 to 26.7 per 1,000,000 persons and from 0.8 to 2.7 per 1,000,000 persons, respectively. The male gender is predominant in both forms. All except one patient showed evidence of cardiomyopathy. This epidemiological data requires attention, not only to increase the effort for the clinical management and earlier diagnosis, but also to underline the need for the disease-specific treatments., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Aims: To perform evaluation of widely embraced bone scintigraphy-based non-biopsy diagnostic criteria (NBDC) for ATTR amyloid cardiomyopathy (ATTR-CM) in clinical practice, and to refine serum free light chain (sFLC) ratio cut-offs that reliably exclude monoclonal gammopathy (MG) in chronic kidney disease., Methods and Results: A multi-national retrospective study of 3354 patients with suspected or histologically proven cardiac amyloidosis (CA) referred to specialist centres from 2015 to 2021; evaluations included radionuclide bone scintigraphy, serum and urine immunofixation, sFLC assay, eGFR measurement and echocardiography. Seventy-nine percent (1636/2080) of patients with Perugini grade 2 or 3 radionuclide scans fulfilled NBDC for ATTR-CM through absence of a serum or urine monoclonal protein on immunofixation together with a sFLC ratio falling within revised cut-offs incorporating eGFR; 403 of these patients had amyloid on biopsy, all of which were ATTR type, and their survival was comparable to non-biopsied ATTR-CM patients (p = 0.10). Grade 0 radionuclide scans were present in 1091 patients, of whom 284 (26%) had CA, confirmed as AL type (AL-CA) in 276 (97%) and as ATTR-CM in only one case with an extremely rare TTR variant. Among 183 patients with grade 1 radionuclide scans, 122 had MG of whom 106 (87%) had AL-CA; 60/61 (98%) without MG had ATTR-CM., Conclusion: The NBDC for ATTR-CM are highly specific [97% (95% CI 0.91-0.99)] in clinical setting, and diagnostic performance was further refined here using new cut-offs for sFLC ratio in patients with CKD. A grade 0 radionuclide scan all but excludes ATTR-CM but occurs in most patients with AL-CA. Grade 1 scans in patients with CA and no MG are strongly suggestive of early ATTR-type, but require urgent histologic corroboration., Competing Interests: Conflict of interest No COIs are reported in relation to this work. J.D.G. reports consultancy fees from Alnylam, Ionis, Eidos, Pfizer, Attralus, AstraZeneca, and Intellia and receipt of payments for advisory board meetings of Intellia, Attralus, and Ionis/AstraZeneca. M.F. reports consultancy fees from Alnylam, Ionis, Pfizer, Attralus, Alexion, Novo Nordisk A/S, Akcea, BridgeBio, and Intellia. D.F.H. reports speaker fees from Alnylam and Pfizer. C.J.W. reports honoraria from Akcea, Alnylam, Novartis, and Pfizer. A.D.W. reports consulting fees from Alexia, AstraZeneca, Janssen, Attralus, and Prothena. F.P. reports consultancy fees from Alnylam and Pfizer and support for travel and meetings from Pfizer. F.C. reports consultancy fees from Alnylam, Pfizer, and Novo Nordisk and receipt of support for travel and meetings from Pfizer. E.B. reports fiduciary role in BMS and Sanofi. A.G.P. reports consultancy fees from Pfizer and support for travel and meetings from Alnylam. S.L. reports participation in advisory board for Alnylum and receipt of support for travel and meetings from Alnylum and Pfizer., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aim: Epidemiology of wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) remains poorly defined. A better characterization of pathways leading to ATTRwt-CA diagnosis is of key importance, and potentially informative of disease course and prognosis. The aim of this study was to describe the characteristics of contemporary pathways leading to ATTRwt-CA diagnosis, and their potential association with survival., Methods and Results: This was a retrospective study of patients diagnosed with ATTRwt-CA at 17 Italian referral centres for CA. Patients were categorized into different 'pathways' according to the medical reason that triggered the diagnosis of ATTRwt-CA (hypertrophic cardiomyopathy [HCM] pathway, heart failure [HF] pathway, incidental imaging or incidental clinical pathway). Prognosis was investigated with all-cause mortality as endpoint. Overall, 1281 ATTRwt-CA patients were included in the study. The diagnostic pathway leading to ATTRwt-CA diagnosis was HCM in 7% of patients, HF in 51%, incidental imaging in 23%, incidental clinical in 19%. Patients in the HF pathway, as compared to the others, were older and had a greater prevalence of New York Heart Association (NYHA) class III-IV and chronic kidney disease. Survival was significantly worse in the HF versus other pathways, but similar among the three others. In multivariate model, older age at diagnosis, NYHA class III-IV and some comorbidities but not the HF pathway were independently associated with worse survival., Conclusions: Half of contemporary ATTRwt-CA diagnoses occur in a HF setting. These patients had worse clinical profile and outcome than those diagnosed either due to suspected HCM or incidentally, although prognosis remained primarily related to age, NYHA functional class and comorbidities rather than the diagnostic pathway itself., (© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aim of the study was to explore frailty and quality of the relationship with the caregiver in a cohort of older patients with transthyretin cardiac amyloidosis (ATTR-CA). Sixty-eight consecutive ATTR-CA patients were recruited and assessed for frailty, depressive symptoms, quality of the relationship in terms of social support, or conflict toward caregivers, New York Heart Association Class (NYHA), and National Amyloid Center score (NAC Score) for grading disease severity. Results showed that 10% of patients were frail. Depressive symptoms were present in 46% of patients. Regression analyses showed that both mFI and depression were associated with worse perception of social support, and that mFI and NAC score were associated with higher levels of conflict perceived in the caregivers' relationship. Overall, the mFI score was associated with worse perceived social support and caregiver relationship quality. Tertiary care heart failure clinics should actively support the patient-caregiver relationship to improve quality of life., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The p.Val142Ile variant in transthyretin (encoded by the TTR gene) is the most common genetic cause of transthyretin-related amyloidosis. This allele is particularly prevalent in communities ofAfrican descent compared with populations of different ancestries, where its frequency is two orders of magnitude lower. For this reason, p.Val142Ile has always been considered an "African" variant, with limited studies performed on individuals of European descent. However, recent reports of higher-than-expected prevalence in European-ancestry populations question the African specificity of this allele. Here we show that the high recurrence of p.Val142Ile in central Italy is due to a founder effect and not to recent admixture from African populations, highlighting how this may be the case in other communities. This suggests a probable underestimate of the global prevalence of p.Val142Ile, and further emphasizes the importance of routine inclusion of TTR in gene panels used for clinical genetic testing in hypertrophic cardiomyopathy (independently of the patient's geographical origin), that transthyretin-related amyloidosis can mimic., (© 2022. The Author(s), under exclusive licence to European Society of Human Genetics.)

The subjective perception of cardiac symptom severity is considered a main treatment target in the management of transthyretin-related cardiac amyloidosis (CA), as opposed to objective prognostic markers such as N-terminal pro b-type natriuretic peptide (NT-proBNP), which objectively reflects the severity of heart disease. Nevertheless, anxious and depressive symptoms in patients with CA might affect subjects perceptions of disease, creating a potential gap between objective and subjective parameters. We assess the impact of such bias in consecutive patients with CA. A total of 60 patients aged 62 to 88 years with CA were recruited. The level of anxiety and depression was measured by the Hospital Anxiety and Depression Scale and the subjective perception of symptoms severity by the Kansas City Cardiomyopathy Questionnaire (KCCQ). Finally, NT-proBNP plasma levels at rest and glomerular filtration rate were measured. Nearly 1/2 of the patients (48%) reported clinically relevant levels of psychologic symptoms. Higher levels of anxious and depressive symptoms were significantly linked to lower KCCQ scores. Furthermore, the relation between NT-proBNP and KCCQ was significant only when anxious and depressive symptoms were low (β = -0.86, p = 0.002; β = -0.86, p = 0.002, respectively) and medium (β = -0.49, p = 0.004; β = -0.45, p = 0.004, respectively) but was otherwise lost. Depression and anxiety in patients with transthyretin-related CA required assessment and management. In conclusion, patients with depression/anxiety have a clear disconnect between their personal assessment and objective measures of cardiac symptoms, with a major influence on the patients' wellbeing and on their subjective response to treatments in clinical trials., Competing Interests: Disclosures The authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The aim of this study is to evaluate the prognostic value of cardiopulmonary testing (CPET) in a cohort of patients with transthyretin cardiac amyloidosis (ATTR-CA). ATTR-CA is associated with a progressive reduction in functional capacity. The prognostic role of CPET parameters and in particular of normalized peak VO2 (%ppVO2) remains to be thoroughly evaluated. In this study, 75 patients with ATTR-CA underwent cardiological evaluation and CPET in a National Referral Center for cardiac amyloidosis (Careggi University Hospital, Florence). Fifty-seven patients (76%) had wild-type ATTR. Median age was 80 (75-83) years, 68 patients (91%) were men. Peak oxygen consumption (14.1 ± 4.1 ml/kg/min) and %ppVO 2 (68.4 ± 18.8%) were blunted. Twenty-seven (36%) patients had an abnormal pressure response to exercise. After a median follow-up of 25 (12-31) months, the composite outcome of death or heart failure hospitalization was registered in 19 (25.3%) patients. At univariate analysis %ppVO 2 was a stronger predictor for the composite outcome than peak VO 2 . %ppVO 2 and NT-proBNP remained associated with the composite outcome at multivariate analysis. The optimal predictive threshold for %ppVO 2 was 62% (sensitivity: 71%; specificity: 68%; AUC: 0.77, CI 0.65-0.88). Patients with %ppVO 2  ≤ 62%and NT-proBNP > 3000 pg had a worse prognosis with 1- and 2-year survival of 69 ± 9% and 50 ± 10%, respectively. CPET is a safe and useful prognostic tool in patients with ATTR-CA. CPET may help to identify patients with advanced disease that may benefit from targeted therapy., (© 2022. The Author(s), under exclusive licence to Società Italiana di Medicina Interna (SIMI).)

Patients with ATTR cardiac amyloidosis (ATTR-CA) face rare disease that could negatively influence psychological well-being with consequences on the course of the disease and quality of life. However, to date, no study analyzed the prevalence of anxiety and depression in patients with ATTR-CA and which clinical and sociodemographic characteristics are linked with these psychopathological conditions. A total of 109 consecutive patients (83% males) aged 62-90 years with ATTR-CA were recruited. In order to better understand the prevalence of anxiety and depression in ATTR-CA, a control group composed by 33 individuals equaling gender, education, and age were recruited. The level of anxiety and depression was measured using the Italian version of the Hospital Anxiety and Depression Scale (HADS). Sociodemographic and clinic characteristics were registered. Almost half of patients (49%) reported a clinical level of depression or anxiety, or both. ATTR-CA patients reported higher levels of anxiety and depression than control group. Results showed that older patients with ATTR-CA, especially females, with more advanced disease could be more at risk to develop an anxious disorder. Furthermore, being a woman, and presenting with a greater severity of symptoms, would appear to be a risk factor for developing a depressive disorder. Overall, these results highlighted the high presence of anxiety and depression in ATTR-CA patients, suggesting to physicians to pay attention to the psychological well-being of ATTR-CA patients. In fact, a psychological support for patients with high level of psychopathological disease could reduce disease burden and improve quality of life in ATTR-CA population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Smorti, Ponti, Soffio, Argirò, Perfetto, Zampieri, Mazzoni, Tomberli, Allinovi, Di Mario, Olivotto and Cappelli.)

Orthopaedic manifestations of wild-type transthyretin amyloidosis are frequent and characteristic, including idiopathic bilateral carpal tunnel syndrome, idiopathic lumbar canal stenosis, atraumatic rupture of the brachial biceps tendon, and, more rarely, finger disease and rotator cuff. These manifestations often coexisting in the same patient, frequently male and aged, steadily precede cardiac involvement inducing a rapidly progressive heart failure with preserved ejection fraction. Although transthyretin cardiac amyloidosis remains a cardiac relevant disease, these extracardiac localisation may increase diagnostic suspicion and allow for early diagnosis assuming the role of useful diagnostic red flags, especially in light of new therapeutic opportunities that can slow or stop the progression of the disease. For the cardiologist, the recognition of these extracardiac red flags is of considerable importance to reinforce an otherwise less emerging diagnostic suspicion. For orthopedists and rheumatologists, the presence in an old patient with or without clinical manifestations of cardiovascular disease, of an unexpected and inexplicable constellation of musculoskeletal symptoms, can represent a fundamental moment for an early diagnosis and treatment is improving a patient's outcome.

Background: Multiple myeloma (MM) is a malignant neoplasm associated with kidney involvement in nearly half of the patients. Cast nephropathy, monoclonal immunoglobulin deposition disease (MIDD), and light chain (AL) amyloidosis are the most common monoclonal immunoglobulin-mediated causes of renal injury. Cardiac involvement is also present in MM, characterized by restrictive cardiomyopathy generated by light chain deposit or amyloid. Thromboembolic complications such as deep vein thrombosis or pulmonary embolism are also described., Case Presentation: We present an unusual multidisciplinary case of a woman with a newly diagnosed MM associated with severe proteinuria and high natriuretic peptide. A renal and fat pad biopsy with Congo red staining were performed but amyloid deposition was not discovered. While immunofluorescence on fresh frozen unfixed tissue was not contributory, the immunofluorescence on fixed tissue and electron microscopy revealed the correct diagnosis. During subsequent investigations, two intracardiac right-sided masses and massive pulmonary embolism were also detected., Conclusions: This case highlights that multiple organ involvement in patients with MM may result from a combination of paraprotein-dependent and -independent factors. Moreover, renal diseases induced by monoclonal gammopathies are a group of complex and heterogeneous disorders. Their subtle presentation and their potential multiorgan involvement require the expertise of a multidisciplinary team able to provide the most appropriate diagnostic and therapeutic assessment., (© 2022. The Author(s).)

Cardiac amyloidosis (CA), caused by the deposition of insoluble amyloid fibrils, impairs different cardiac structures, altering not only left ventricle (LV) systo-diastolic function but also atrial function and the conduction system. The consequences of the involvement of the cardiac electrical system deserve more attention, as well as the study of the underlying molecular mechanisms. This is an issue of considerable interest, given the conflicting data on the effectiveness of conventional antiarrhythmic strategies. Therefore, this review aims at summarizing the arrhythmic burden related to CA and the available evidence on antiarrhythmic treatment in this population.

Background: Low QRS voltages (LQRSVs) are a common electrocardiographic feature in patients with light chain amyloidosis (AL) and transthyretin amyloidosis (ATTR) cardiac amyloidosis (CA)., Objectives: The aim of this study was to identify clinical and echocardiographic correlates of LQRSV and to investigate their prognostic significance in patients with CA., Methods: This was a multicenter, retrospective study performed in 6 CA referral centers including consecutive patients with AL and ATTR CA. LQRSVs were defined as a QRS amplitude ≤5 mm (0.5 mV) in all peripheral leads. The study outcome was cardiovascular (CV) mortality., Results: Overall, 411 (AL CA: n = 120, ATTR CA: n = 291) patients were included. LQRSVs were present in 66 (55%) patients with AL CA and 103 (35%) with ATTR CA ( P < 0.001). In AL CA, LQRSVs were independently associated with younger age ( P = 0.015), higher New York Heart Association functional class ( P = 0.016), and natriuretic peptides ( P = 0.041); in ATTR CA, LQRSVs were independently associated with pericardial effusion ( P = 0.008) and lower tricuspid annulus peak systolic excursion ( P = 0.038). During a median follow-up of 33 months (Q1-Q3: 21-46), LQRSVs independently predicted CV death in both AL CA (HR: 1.76; 95% CI: 2.41-10.18; P = 0.031) and ATTR CA (HR: 2.64; 95% CI: 1.82-20.17; P = 0.005). Together with the National Amyloidosis Centre (NAC) staging, LQRSVs provided incremental prognostic value in ATTR CA (AUC for NAC model: 0.83 [95% CI: 0.77-0.89]; AUC for NAC + LQRSV model: 0.87 [95% CI: 0.81-0.93]; P = 0.040)., Conclusions: LQRSVs are common but not ubiquitous in CA; they are more frequent in AL CA than in ATTR CA. LQRSVs reflect an advanced disease stage and independently predict CV death. In ATTR CA, LQRSVs can provide incremental prognostic accuracy over the NAC staging system in patients with intermediate risk., Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2022 The Authors.)

Background: Cardiac amyloidosis (CA) is cardiomyopathy with a hypertrophic phenotype characterised by diffuse deposition of anomalous fibrillar proteins in the extracellular matrix., Objectives: To evaluate the prevalence and diagnostic value of extra left ventricle echocardiographic findings in patients with left ventricular (LV) hypertrophic phenotype and amyloid deposition., Methods: A group of 146 patients with LV thickness ≥15 mm were enrolled: 70 patients who received a definite diagnosis of sarcomeric hypertrophic cardiomyopathy (HCM group) and 76 patients with transthyretin cardiac amyloidosis (CA group). Echocardiographic analysis of crista terminalis (CriT), atrio-ventricular plane (AVP), mitro-aortic lamina (MAL), anterior ascending aortic wall, interatrial septum (IAS), Eustachian valve (EusV) and coumadin ridge (CouR) was performed in all patients, and these structures were compared among the two groups., Results: CA group showed significantly higher dimensions of CriT, IAS, CouR, AVP, MAL and IAS compared to the HCM group. The logistic analysis showed that LV EF, LV septal thickness, CriT presence, CriT area, MAL and IAS were all predictors of CA in univariate analyses. The stepwise multivariate analysis showed independent predictors of CA: CriT area, MAL and LVEF. According to areas under the receiver operating characteristic curves the best cut-off values to determine CA were identified (IAS > 9 mm, MAL > 7 mm, CriT > 9 mm 2 ). Among these 3 independent predictors, IAS > 9 mm had the best specificity (96%) and positive predictive value (93%) in identifying CA., Conclusions: evidence of extra left ventricle sites of amyloid deposition is a frequent finding in CA. In the context of hypertrophic phenocopies, an increased thickness of IAS, and/or CT and/or MAL should suggest a diagnosis of transthyretin CA.

Cardiac amyloidosis is an infiltrative disease characterized by extracellular deposition of insoluble amyloid fibrils in the heart leading to organ dysfunction. Despite recent diagnostic advances, the diagnosis of cardiac amyloidosis is often delayed or even missed. Furthermore, a long diagnostic delay is associated with adverse outcomes, with the early diagnosed patients showing the longest survival. In this narrative review we aimed to summarize the 'red flags' that may facilitate the correct diagnosis. The red flags may be classified as clinical, biohumoral, electrocardiographic, echocardiographic, and cardiac magnetic resonance features and should promptly raise the suspicion of cardiac amyloidosis in order to start a correct diagnostic pathway and targeted treatment strategies that may improve patients' outcomes., (Copyright © 2022 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Aim: To investigate the prevalence of amyloid cardiomyopathy (AC) and the diagnostic accuracy of echocardiographic red flags of AC among consecutive adult patients undergoing transthoracic echocardiogram for reason other than AC in 13 Italian institutions., Methods and Results: This is an Italian prospective multicentre study, involving a clinical and instrumental work-up to assess AC prevalence among patients ≥55 years old with an echocardiogram suggestive of AC (i.e. at least one echocardiographic red flag of AC in hypertrophic, non-dilated left ventricles with preserved ejection fraction). The study was registered at ClinicalTrials.gov (NCT04738266). Overall, 381 patients with an echocardiogram suggestive of AC were identified among a cohort of 5315 screened subjects, and 217 patients completed the investigations. A final diagnosis of AC was made in 62 patients with an estimated prevalence of 29% (95% confidence interval 23%-35%). Transthyretin-related AC (ATTR-AC) was diagnosed in 51 and light chain-related AC (AL-AC) in 11 patients. Either apical sparing or a combination of ≥2 other echocardiographic red flags, excluding interatrial septum thickness, provided a diagnostic accuracy >70%., Conclusion: In a cohort of consecutive adults with echocardiographic findings suggestive of AC and preserved left ventricular ejection fraction, the prevalence of AC (either ATTR or AL) was 29%. Easily available echocardiographic red flags, when combined together, demonstrated good diagnostic accuracy., (© 2022 European Society of Cardiology.)

Aims: The incidence and risk factors of pacemaker (PM) implantation in patients with cardiac amyloidosis (CA) are largely unexplored. We sought to characterize the trends in the incidence of permanent PM and to identify baseline predictors of future PM implantation in light-chain (AL) and transthyretin (ATTR) CA., Methods and Results: Consecutive patients with AL and ATTR-CA diagnosed at participating centres (2017-2020) were included. Clinical data recorded within ±1 month from diagnosis were collected from electronic medical records. The primary study outcome was the need for clinically-indicated PM implantation. Patients with PM (n = 41) and/or permanent defibrillator in situ (n = 13) at CA diagnosis were excluded. The study population consisted of 405 patients: 29.4% AL, 14.6% variant ATTR and 56% wild-type ATTR; 82.5% were male, median age 76 years. During a median follow-up of 33 months (interquartile range 21-46), 36 (8.9%) patients experienced the primary outcome: 10 AL-CA, 2 variant ATTR-CA and 24 wild-type ATTR-CA (p = 0.08 at time-to-event analysis). At multivariable analysis, history of atrial fibrillation (hazard ratio [HR] 3.80, p = 0.002), PR interval (HR 1.013, p = 0.002) and QRS >120 ms (HR 4.7, p = 0.001) on baseline electrocardiogram were independently associated with PM implantation. The absence of these three factors had a negative predictive value of 92% with an area under the curve of 91.8% at 6 months., Conclusion: In a large cohort of AL and ATTR-CA patients, 8.9% received a PM within 3 years after diagnosis. History of atrial fibrillation, PR >200 ms and QRS >120 ms predicted future PM implantation., (© 2022 European Society of Cardiology.)

Cardiac amyloidosis (CA) is due to extracellular myocardial deposition of misfolded proteins resulting in severe cardiac dysfunction and death. The precursors of amyloid fibrils, able of determining a relevant cardiac infiltration, are immunoglobulin-free light chains (AL amyloidosis) and transthyretin (TTR) (both wild and mutated types). The diagnosis of amyloidosis represents a challenge for the clinician given its rarity and its protean clinical presentation, thus an early diagnosis remains a cornerstone for the prognosis of these patients, also in light of the growing available treatments. There is great interest in identifying and applying biomarkers to help diagnose, inform prognosis, guide therapy, and serve as surrogate endpoints in these patients. In AL amyloidosis, biomarkers such as free light chains, natriuretic peptides and troponins are the most extensively studied and validated; they have proved useful in risk stratification, guiding treatment choice and monitoring hematological and organ response. A similar biomarker-based prognostic score is also proposed for ATTR amyloidosis, although studies are small and need to be validated for wild-type and mutant forms., (© 2022. The Author(s).)

Background: The valine-to-isoleucine substitution (Val122Ile) is the most common variant of transthyretin (TTR) amyloidosis in the United States, affecting primarily individuals of African descent. This variant has been identified recently in a cluster of white individuals in Italy., Methods and Results: Clinical phenotype and chamber performance of Black and white individuals with Val122Ile TTR cardiac amyloidosis (ATTR-CA) were compared. Compared to white patients (n = 17), Black individuals (n = 53) had lower systolic blood pressures (110 vs 131 mmHg, <0.001), reduced pulse pressures (41 vs 58 mmHg; P < 0.001), and impaired renal function (eGFR 46 vs 67 mL/min/1.73m 2 ; P < 0.001) at presentation. Systolic properties and arterial elastance were similar. Black patients had end-diastolic pressure-volume relationships that were shifted upward and leftward relative to those of white patients, indicating reduced left ventricular chamber capacitance. Pressure-volume area at a left ventricular end-diastolic pressure of 30 mmHg was lower in Black than in white individuals (8055 mmHg/mL vs 11,538 mmHg/mL; P = 0.008)., Conclusion: Despite presenting at ages similar to those of white patients, Black individuals with Val122Ile-associated ATTR-CA had a greater degree of cardiac chamber dysfunction at the time of diagnosis due to impaired ventricular capacitance. Whether these differences are attributable to amyloidosis or other cardiovascular disease requires further study., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Systemic amyloidosis arises from monoclonal CD38+ plasma cells that produce misfolded immunoglobulin light chains, which form amyloid fibrils that are deposited into different tissues, leading to organ damage. Daratumumab is a human IgG/k monoclonal antibody that targets CD38, a glycoprotein uniformly expressed on human plasma cells. Daratumumab has been utilized in recent years with unprecedented responses in multiple myeloma. In patients with relapsed or refractory AL amyloidosis, daratumumab has shown promising efficacy in terms of hematologic responses and improvement in organ function. Here, we report real-life treatment with Daratumumab in 33 AL amyloidosis patients treated within the Regional Tuscan Myeloma network at 5 centers with associated MGUS or SMM ( n = 15) or symptomatic MM ( n = 18). Patients were treated at relapsed/refractory disease stages ( n = 29) with a median of one previous line of therapy or at diagnosis ( n = 4). Daratumumab showed good efficacy, representing 60% of good hematological responses and 50% of organ responses in a real-life population of patients with an acceptable toxicity profile.

We aimed to ascertain whether sex-related differences are relevant to clinical presentation, cardiac phenotype and all-cause mortality in different types of cardiac amyloidosis, a field still poorly investigated. Medical files from consecutive patients diagnosed with cardiac amyloidosis between 2000 and 2020, at Careggi University Hospital, were retrospectively evaluated. Over this period, 259 patients (12% females) were diagnosed with wild type transthyretin amyloidosis (wtATTR), 52 (25% females) with hereditary transthyretin amyloidosis (hATTR) and 143 (47% females) with light chain amyloidosis (AL). Women with wtATTR, compared to men, were significantly older at the time of diagnosis and showed higher National Amyloidosis Centre score, thicker normalized interventricular septum, higher diastolic dysfunction and worse right ventricular function. Females with hATTR and AL had lower normalized cardiac mass compared to men, otherwise, bio-humoral parameters, NYHA class, and ECG characteristics were similar. Comparing females and male with wtATTR, hATTR and AL, no differences in Kaplan-Meier curves for all-cause mortality were observed with regard to sex, p-value >0.05. In conclusion, we did not observe major differences in clinical expression related to sex in different types of cardiac amyloidosis: specifically, all-cause mortality was not affected. Nevertheless, women with wtATTR had echocardiographic signs of more advanced disease and higher NAC score at diagnosis suggesting a possible later recognition of disease compared to men., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Amyloid transthyretin (ATTR) amyloidosis is caused by the systemic deposition of transthyretin molecules, either normal (wild-type ATTR, ATTRwt) or mutated (variant ATTR, ATTRv). ATTR amyloidosis is a disease with a severe impact on patients' quality of life (QoL). Nonetheless, limited attention has been paid to QoL so far, and no specific tools for QoL assessment in ATTR amyloidosis currently exist. QoL can be evaluated through patient-reported outcome measures (PROMs), which are completed by patients, or through scales, which are compiled by clinicians. The scales investigate QoL either directly or indirectly, i.e., by assessing the degree of functional impairment and limitations imposed by the disease., Design: Search for the measures of QoL evaluated in phase 2 and phase 3 clinical trials on ATTR amyloidosis., Results: Clinical trials on ATTR amyloidosis have used measures of general health status, such as the Short Form 36 Health Survey (SF-36), or tools developed in other disease settings such as the Kansas City Cardiomyopathy Questionnaire (KCCQ) or adaptations of other scales such as the modified Neuropathy Impairment Score +7 (mNIS+7)., Conclusions: Scales or PROMs for ATTR amyloidosis would be useful to better characterize newly diagnosed patients and to assess disease progression and response to treatment. The ongoing ITALY (Impact of Transthyretin Amyloidosis on Life qualitY) study aims to develop and validate 2 PROMs encompassing the whole phenotypic spectrum of ATTRwt and ATTRv amyloidosis, that might be helpful for patient management and may serve as surrogate endpoints for clinical trials., (© 2021 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting.)

Aims: The use of beta-blocker therapy in cardiac amyloidosis (CA) is debated. We aimed at describing patterns of beta-blocker prescription through a nationwide survey., Methods and Results: From 11 referral centres, we retrospectively collected data of CA patients with a first evaluation after 2016 (n = 642). Clinical characteristics at first and last evaluation were collected, with a focus on medical therapy. For patients in whom beta-blocker therapy was started, stopped, or continued between first and last evaluation, the main reason for beta-blocker management was requested. Median age of study population was 77 years; 81% were men. Arterial hypertension was found in 58% of patients, atrial fibrillation (AF) in 57%, and coronary artery disease in 16%. Left ventricular ejection fraction was preserved in 62% of cases, and 74% of patients had advanced diastolic dysfunction. Out of the 250 CA patients on beta-blockers at last evaluation, 215 (33%) were already taking this therapy at first evaluation, while 35 (5%) were started it, in both cases primarily because of high-rate AF. One-hundred-nineteen patients (19%) who were on beta-blocker at first evaluation had this therapy withdrawn, mainly because of intolerance in the presence of heart failure with advanced diastolic dysfunction. The remaining 273 patients (43%) had never received beta-blocker therapy. Beta-blockers usage was similar between CA aetiologies. Patients taking vs. not taking beta-blockers differed only for a greater prevalence of arterial hypertension, coronary artery disease, AF, and non-restrictive filling pattern (P < 0.01 for all) in the former group., Conclusions: Beta-blockers prescription is not infrequent in CA. Such therapy may be tolerated in the presence of co-morbidities for which beta-blockers are routinely used and in the absence of advanced diastolic dysfunction., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

The diagnosis of cardiac amyloidosis (CA) is challenging because of its phenotypic heterogeneity, multi-organ involvement often requiring the interaction among experts in different specialties and subspecialties, the lack of a single non-invasive diagnostic tool, and limited awareness in the medical community. Recent studies have challenged the dogma of CA as a rare, incurable disease, and have redefined the epidemiology and therapeutic options for this condition. Missing or delaying the diagnosis may have a profound impact on patient outcome, as potentially life-saving treatments may be omitted or delayed, particularly chemotherapy in the case of amyloid light-chain amyloidosis. For a timely identification, clinical cardiologists should be able to recognize the "red flags" prompting a dedicated diagnostic work-up. Cardiologists could also face the challenge of making decisions about drug and device therapies for patients with known CA. The present consensus document aims to provide a practical guide and an organizational framework for professionals belonging to the Tuscan network of hospital cardiologists.

Whether diagnostic timing in transthyretin (TTR) cardiac amyloidosis (CA) predisposes patients to worse outcomes is unresolved. We aimed to describe the long-term association of diagnostic timing (time from first onset of symptoms consistent with CA leading to medical contact to definitive diagnosis) with mortality in patients with wild-type TTR-CA (ATTRwt-CA). Overall, we reviewed the medical records of 160 patients seen at a tertiary care amyloidosis unit from January 1, 2016, to January 1, 2020 (median [interquartile range] follow-up, 21 [10 to 34] months), and compared them by survival. Median diagnostic timing was 4 (2 to 12) months and was longer in nonsurvivors (9 [3 to 15] vs 3 [1 to 7] months; P<.001). Patients diagnosed 6 or more months after symptom onset had higher mortality, with a median survival of 30 months (95% CI, 22 to 37 months). On Cox multivariable analysis, timing was independently associated with all-cause mortality (hazard ratio per month increase, 1.049 [95% CI, 1.017 to 1.083]) together with age at diagnosis, disease stage, New York Heart Association class, and coronary artery disease. In conclusion, diagnostic timing of ATTRwt-CA is associated with mortality. Timely diagnosis is warranted whenever "red flags" are present., (Copyright © 2021 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Background: Amyloidosis is considered a rare heterogeneous condition comprising different entities. Epidemiological data are limited and often controversial. We aimed to examine epidemiological changes in amyloidosis diagnosed over a 20-year period at a tertiary referral centre for amyloidosis., Methods: We retrospectively reviewed medical files from all patients diagnosed with amyloidosis between January 2000 and December 2019, at Careggi University Hospital, Florence, Italy. Diagnosis of amyloidosis was performed as per current clinical practice and scientific evidence at the time of patient evaluation., Results: We reported data on 654 consecutive patients: 274 (42%) wild type transthyretin amyloidosis (wtATTR), 68 (10%) genetic variant amyloidosis (vATTR), 281 (43%) light-chain amyloidosis (AL) and 31 (5%) serum amyloid A amyloidosis (AA). With limited fluctuations, the absolute number of new AL diagnosis increased during the 20-year period. wtATTR was unrecognized before 2009 but represented by far the most common aetiology at the end of the observation period. AA represented a residual diagnosis throughout the entire examined period., Conclusions: Following a rapid and marked increase in the number of new diagnoses over the last decade, ATTR represents by far the most common type of amyloidosis in our regional centre. These data contrasts with recent reports from national referral institutions and may help shed light on the epidemiology of the disease at the community level., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Recent evidence suggests that carpal tunnel syndrome (CTS) and brachial biceps tendon rupture (BBTR) represent red flags for ATTR cardiac amyloidosis (ATTR-CA). The prevalence of upper limb tenosynovial complications in conditions entering differential diagnosis with CA, such as HCM or Anderson-Fabry disease (AFD), and hence their predictive accuracy in this setting, still remains unresolved., Objective: To investigate the prevalence of CTS and BBTR in a consecutive cohort of ATTR-CA patients, compared with patients with HCM or AFD and with individuals without cardiac disease history., Participants: Consecutive patients with a diagnosis of ATTR-CA, HCM and AFD were evaluated. A control group of consecutive patients was recruited among subjects hospitalized for noncardiac reasons and no cardiac disease history. The presence of BBTR, CTS or prior surgery related to these conditions was ascertained., Results: 342 patients were prospectively enrolled, including 168 ATTR-CA (141 ATTRwt, 27 ATTRm), 81 with HCM/AFD (N = 72 and 9, respectively) and 93 controls. CTS was present in 75% ATTR-CA patients, compared with 13% and 10% of HCM/AFD and controls (P = 0.0001 for both comparisons). Bilateral CTS was present in 60% of ATTR-CA patients, while it was rare (2%) in the other groups. BBTR was present in 44% of ATTR-CA patients, 8% of controls and 1% in HCM/AFD., Conclusions: CTS and BBTR are fivefold more prevalent in ATTR-CA patients compared with cardiac patients with other hypertrophic phenotypes. Positive predictive accuracy for ATTR-CA is highest when involvement is bilateral. Upper limb assessment of patients with HCM phenotypes is a simple and effective way to raise suspicion of ATTR-CA., (© 2020 The Association for the Publication of the Journal of Internal Medicine.)