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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.)

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: 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.)

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.)

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.)

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: 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.)

Systemic amyloidosis encompasses a variety of diseases characterized by extracellular deposition of protein-derived fibrils in different tissues and organs. Immunoglobulin light-chain (AL) and transthyretin (ATTR) amyloid are the two types that more commonly affect the heart and in both subtypes cardiac involvement is the main determinant of prognosis. Recently, several studies have suggested that Cardiac Amyloidosis (CA) and Aortic Stenosis (AS) can coexist more frequently than previously suspected with prevalence ranging from 5,6% to 16% in different cohorts. The unexpected high prevalence of CA in AS and the availability of potentially effective treatment in CA should push us to carefully investigate elderly patients with aortic valve stenosis in order to identify those with coexistent amyloidosis. While the motivation to exclude amyloidosis was in the past their exclusion from active treatment of the valve disease, judged as futile because of their poor unavoidable prognosis, the improved therapeutic options available challenges this conservative approach. Aim of this review is to identify the triggers to investigate AS patients at risk of having concomitant ATTR-CA, to propose a diagnostic path to reach diagnosis and to discuss the changes in the therapeutic strategy caused by this discovery in the era of TAVR and active pharmacological treatments to slow down disease progression., Competing Interests: Declaration of competing interest None declared., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to assess the diagnostic accuracy of bone scintigraphy in a large multicenter cohort of patients with cardiac amyloidotic involvement and Phe64Leu transthyretin (TTR) mutation., Background: Diagnostic accuracy of bone scintigraphy for transthyretin-related cardiac amyloidosis (TTR-CA) is considered extremely high, enabling this technique to be the noninvasive diagnostic standard for TTR-CA. Nevertheless, this approach has not been systematically validated across the entire spectrum of TTR mutations., Methods: A total of 55 patients with Phe64Leu TTR mutation were retrospectively analyzed and evaluated between 1993 and 2018 at 7 specialized Italian tertiary centers. Cardiac involvement was defined as presence of an end-diastolic interventricular septum thickness ≥12 mm, without other possible causes of left ventricular hypertrophy (i.e., arterial hypertension or valvulopathies). A technetium-99m (99mTc)-diphosphonate (DPD) or 99mTc-hydroxyl-methylene-diphosphonate (HMDP) bone scintigraphy was reviewed, and visual scoring was evaluated according to Perugini's method., Results: Among 26 patients with definite cardiac involvement, 19 underwent 99mTc-DPD or 99mTc-HMDP bone scintigraphy. Of them, 17 (89.5%) patients had low or absent myocardial bone tracer uptake, whereas only 2 (10.5%) showed high-grade myocardial uptake. The sensitivity and the accuracy of bone scintigraphy in detecting TTR-CA were 10.5% and 37%, respectively. Patients with cardiac involvement and low or absent bone tracer uptake were similar to those with high-grade myocardial uptake in terms of age, sex, and electrocardiographic and echocardiographic findings., Conclusions: The sensitivity of bone scintigraphy (DPD and HMDP) in detecting TTR-CA is extremely low in patients with Phe64Leu TTR mutation, suggesting the need to assess diagnostic accuracy of bone scintigraphy to identify cardiac involvement across a wider spectrum of TTR mutations., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The severity of heart disease varies widely among patients with transthyretin-related cardiac amyloidosis (ATTR-CA) at presentation, and availability of tools able to predict prognosis is essential for clinical and research purposes. Currently, two biomarker-based staging systems are available. The aim of this study was to compare their predictive performance., Methods: A total of 175 patients diagnosed with ATTR-CA (133 wild-type and 42 hereditary) were stratified into different stages based on 2 systems: the first system included N-terminal pro-B-type natriuretic peptide (NT-proBNP) and estimated glomerular filtration rate (eGFR), and the second one included NT-proBNP and troponin I (TnI). Survival estimates and age-adjusted survival for all-cause mortality were analysed over a median follow-up of 27 months (interquartile range 16-43 months)., Results: Predictive performance was more accurate when NT-proBNP and eGFR were used, resulting in effective survival stratification: 64.4 months for stage 1, 44.6 months for stage 2, and 20.5 months for stage 3 (P < 0.01 for stages 1 vs 2; P < 0.0001 for stages 1 vs 3; P < 0.0001 stages 2 vs 3). The combination of NT-proBNP and TnI was unable to effectively differentiate survival: 64.5 months for stage 1, 50.9 months for stage 2, and 27.3 months for stage 3 (P = 0.223 for stages 1 vs 2; P < 0.0001 for stages 1 vs 3; P < 0.0001 for stages 2 vs 3). The same results were seen after age adjustment., Conclusions: A staging system using NT-proBNP and eGFR had better prognostic accuracy for ATTR-CA patients compared with one using NTproBNP and TnI., (Copyright © 2019 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: Full body scintigraphy using bone tracers plays an important role in defining the type of amyloidosis and in diagnosing the heart involvement (cardiac amyloidosis, CA). No study has been conducted to explore lung retention (LR) in CA and its correlation to heart retention (HR).We evaluated LR in patients undergoing 99mTc-HMDP scintigraphy during evaluation for suspected CA., Methods and Results: We enrolled 93 suspected CA patients. Patients underwent a complete diagnostic work up. After diagnostic process 82 patients resulted affected by certain CA (20 AL and 62 TTR), while 11 subjects showed left ventricular hypertrophy (LVH) not caused by CA. 99mTc-HMDP cardiac uptake was evaluated using the Perugini visual score while the modified Janssen score was used for LR estimation (grade 0 no uptake, grade 1 less than ribs, grade 2 more than ribs)., Results: 99mTc-HMDP LR was observed in 1/20 AL patient (5%), while 36/62 (58%) TTR patients showed LR with 29 grade 1 (47%) and 7 grade 2 (11%). No LR was observed in patients with LVH and no CA. LR was not evident in patients without HR, present in 1/3 (33%) of the patients with Perugini 1 HR and 11/24 (46%) and 26/36 (72%) of the patients showing respectively a Perugini 2 and a Perugini 3., Conclusion: 99mTc-HMDP scintigraphy shows LR in about 60% of TTR subjects, related to the grade of HR. In AL amyloidosis LR is less frequent than in TTR amyloidosis suggesting an aetiological tropism that seems comparable to the already known TTR related cardiac tropism., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: In light-chain (AL) cardiac amyloidosis, the 12-lead electrocardiogram (ECG) reflects myocardial amyloid infiltration with low limb voltages, pseudoinfarction patterns, and conduction abnormalities. Moreover, it is not unusual to see "aspecific" QRS complex abnormalities, such as notches and RsR' pattern in the absence of QRS prolongation, i.e. a fragmentation of QRS complexes (fQRS), that has been associated with myocardial scars and prognosis. Since cardiomyocyte damage and interstitial fibrosis are associated with cardiac amyloid deposition, aim of the present study was to analyze the prevalence and the potential prognostic value of fQRS in patients with cardiac amyloidosis., Methods: We enrolled 375 consecutive untreated patients in whom a first AL amyloidosis diagnosis was concluded between 2008 and 2010, 264 with and 111 without heart involvement. Patients with a positive history of coronary disease were excluded from the analysis., Results: The prevalence of fQRS was significantly higher in patients with cardiac AL amyloidosis (28.5% vs. 11.7%; p=0.0008). After a median follow-up of 561 days, Kaplan-Meier survival analysis revealed a significantly higher mortality in the fQRS group when compared with the "normal" QRS group (p=0.0008). No association was found between the presence of fQRS and the duration of PQ, QRS, and QTc intervals, the presence of peripheral low voltages or pseudonecrosis, NT-proBNP serum levels or cardiac wall thickness., Conclusions: In patients with cardiac AL amyloidosis, the presence of fQRS at diagnosis has an independent prognostic value. Such a simple and cheap analysis in patients' diagnostic work-up may improve diagnosis and prognostic stratification., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)