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We use a simple and effective experimental method for determining the radiative quantum yield of single silicon-vacancy centers (SiV) in nanometric-sized diamonds (NDs). It is based on variations in the luminescence lifetimes of SiVs induced by a controlled change in the NDs' dielectric environment. The deposition of a high refractive index immersion oil on a thin polymer sample containing NDs with an average size of 20 nm induces a noticeable shortening of SiV lifetimes, a clear signature of a strong radiative contribution to the decays. While SiV centers were generally considered to be weak quantum emitters, we demonstrate that single SiV centers in nanodiamonds have a quantum efficiency up to 60 % , under ambient conditions. This quantum efficiency is very similar to that of the negatively charged nitrogen-vacancy centers, which we measured using the same approach. This feature makes single SiV attractive as bright, high-purity single-photon sources for quantum technologies. [ABSTRACT FROM AUTHOR]

Aim and Methods: We conducted a retrospective observational study of the ATTRv heterozygous mutation frequency, phenotype, and all-cause mortality at two cardiac amyloidosis centers in Romania and France., Results: 291 patients were included: 26 Glu54Gln (all Romanian), 200 Val122Ile, 47 Val30Met and 18 Ser77Tyr. On diagnosis, Gu54Gln patients were younger than Val122Ile or late-onset Val30Met (median age: 46 [42-50], 76 [71-80] and 70 [61-76], respectively; p < 0.001) and had more autonomic dysfunction (50 %, 6.3 %, and 7.7 %, respectively; p < 0.001) and similar cardiac symptom profiles. They had fewer conduction disorders (11.5 %) than early-onset Val30Met (76.9 %, p < 0.001) and Ser77Tyr group, notably less cardiac pacemaker present on diagnosis: 3.8 % for Glu54Gln vs. 23.5 % for Ser77Tyr; p = 0.014. Glu54Gln, Val122Ile, late-onset Val30Met and Ser77Tyr patients had similar left ventricular mass and systolic function values. Median survival for Glu54Gln patients was 58.7 years (95 %CI 55.9 - upper bound indeterminable), significantly lower than that of Val122Ile (83.6 years 95 %CI 81.6-85.5, log-rank test p < 0.001), late-onset Val30Met (83.4 years 95 %CI 81.9-84.9, log-rank test p < 0.001) and Ser77Tyr (74.8 years 95 %CI 68.7-80.9, log-rank test p = 0.022). Median survival after diagnosis was 5.7 years for Glu54Gln patients (95 %CI 4.7-6.4)., Conclusion: We established that the Glu54Gln variant has an aggressive, mixed phenotype, with an early onset of autonomic dysfunction and heart failure symptoms. We emphasize the need for systematic genetic testing in patients with ATTR as understanding genotype-phenotype correlations is key for the management and the counseling of patients and their family members., Competing Interests: Declaration of competing interest RJ and RA received speaker fees and unrestricted educational grants from Pfizer and Genesis Pharma., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

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

We report on the design, realization, and experimental investigation by spatially resolved monochromated electron energy loss spectroscopy (EELS) of high-quality-factor cavities with modal volumes smaller than λ 3 , with λ being the free-space wavelength of light. The cavities are based on a slot defect in a 2D photonic crystal slab made up of silicon. They are optimized for high coupling of electrons accelerated to 100 kV to quasi-transverse electrical modes polarized along the slot direction. We studied the cavities in two geometries and took advantage of the deep sub-optical wavelength spatial resolution of the electron microscope and high spectral resolution of the monochromator to comprehensively describe the optical excitations of the slab. The first geometry, for which the cavities have been designed, corresponds to an electron beam traveling along the slot direction. The second consists of the electron beam traveling perpendicular to the slab. In both cases, a large series of modes is identified. The dielectric slot mode energies are measured to be in the 0.8-0.85 eV range, as per design, and surrounded by two bands of dielectric and air modes of the photonic structure. The dielectric even slot modes, to which the cavity mode belongs, are highly coupled to the electrons with up to 3.2% probability of creating a slot photon per incident electron. Although the experimental spectral resolution (around 30 meV) alone does not allow to disentangle cavity photons from other slot photons, the excellent agreement between the experiments and finite-difference time-domain simulations allows us to deduce that among the photons created in the slot, around 30% are stored in the cavity mode. A systematic study of the energy and coupling strength as a function of the photonic band gap parameters permits us to foresee an increase of coupling strength by fine-tuning phase-matching. Our work demonstrates free electron coupling to high-quality-factor cavities with low mode densities and sub-λ 3 modal volumes, making it an excellent candidate for applications such as quantum nano-optics with free electrons.

Understanding and mastering quantum electrodynamics phenomena is essential to the development of quantum nanophotonics applications. While tailoring of the local vacuum field has been widely used to tune the luminescence rate and directionality of a quantum emitter, its impact on their transition energies is barely investigated and exploited. Fluorescent defects in nanosized diamonds constitute an attractive nanophotonic platform to investigate the Lamb shift of an emitter embedded in a dielectric nanostructure with high refractive index. Using spectral and time-resolved optical spectroscopy of single SiV defects, we unveil blue shifts (up to 80 meV) of their emission lines, which are interpreted from model calculations as giant Lamb shifts. Moreover, evidence for a positive correlation between their fluorescence decay rates and emission line widths is observed, as a signature of modifications not only of the photonic local density of states but also of the phononic one, as the nanodiamond size is decreased. Correlative light-electron microscopy of single SiVs and their host nanodiamonds further supports these findings. These results make nanodiamond-SiVs promising as optically driven spin qubits and quantum light sources tunable through nanoscale tailoring of vacuum-field fluctuations.

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

Background and Aims: Self-reported questionnaires are useful for estimating the health-related quality of life (HR-QoL), impact of interventions, and prognosis. To our knowledge, no HR-QoL questionnaire has been developed for cardiac amyloidosis (CA). This study aimed to validate Amylo-AFFECT-QOL questionnaire to assess HR-QoL and its prognostic value in CA., Methods: A self-reported questionnaire, "Amylo-AFFECT" had been designed and validated for CA symptoms evaluation and screening by physicians. It was adapted here to assess HR-QoL (Amylo-AFFECT-QOL) and its prognostic value in CA. To validate the theoretical model, internal consistency and convergent validity were assessed, particularly correlations between Amylo-AFFECT-QOL and the HR-QoL Minnesota Living Heart Failure (MLHF) questionnaire., Results: Amylo-AFFECT-QOL was completed by 515 patients, 425 of whom (82.5%) had CA. Wild-type and hereditary transthyretin amyloidosis (ATTRwt and ATTRv) and immunoglobulin light-chain amyloidosis (AL) were diagnosed in 47.8, 14.7, and 18.8% of cases, respectively. The best HR-QoL evaluation was obtained with five dimensions: "Heart failure," "Vascular dysautonomia," "Neuropathy," "Ear, gastrointestinal, and urinary dysautonomia," and "Skin or mucosal involvement." The global Amylo-AFFECT-QOL and MLHF scores showed significant positive correlations (rs = 0.72, p < 0.05). Patients with a final diagnosis of CA had a global Amylo-AFFECT-QOL score significantly higher than the control group composed by patients with other diagnoses (22.2 ± 13.6 vs. 16.2 ± 13.8, respectively, p -value < 0.01). According to the Amylo-AFFECT-QOL global results, ATTRv patients' QoL was more affected than AL patients' QoL or ATTRwt patients' QoL. Patients with a higher HR-QoL score had a greater risk of death or heart transplant after 1 year of follow-up (log-rank < 0.01)., Conclusion: Amylo-AFFECT-QOL demonstrates good psychometric properties and is useful for quantifying HR-QoL and estimating CA prognosis. Its use may help to improve overall management of patients with CA., Competing Interests: TD received grants or consultancy fees from Akcea, Alnylam, Pfizer, and GSK. SO received honoraria from Pfizer. BF received consultancy fees from Pfizer. EI received honoraria from Pfizer and Janssen-Cilag. RG received honoraria from SANOFI. AB received consultancy fees from Pfizer, Novartis, Vifor Pharma, and AstraZeneca. The remaining 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 Kharoubi, Bézard, Broussier, Galat, Gounot, Poullot, Molinier-Frenkel, Fanen, Funalot, Itti, Lemonnier, Sing Chadha, Guendouz, Mallet, Zaroui, Audard, Audureau, Le Corvoisier, Hittinger, Planté Bordeneuve, Lefaucheur, Amiot, Bequignon, Bartier, Leroy, Teiger, Oghina and Damy.)

Objective: To evaluate the real-life use of a modified Gillmore algorithm with a "one-stop-shop" approach, bone scintigraphy (BS), a monoclonal gammopathy test (GT), a salivary gland biopsy (SGB), and genetic testing performed at the same time for the diagnosis of cardiac amyloidosis at the French National Reference Centre for Cardiac Amyloidosis (Henri Mondor Hospital, Créteil, France)., Methods: This retrospective cohort study included a total of 1222 patients with suspected amyloidosis who underwent BS and GT between June 2008 and May 2019., Results: Of 1222 patients, 349 had no cardiac uptake on BS and negative GT (BS-/GT-), 276 were BS-/GT positive (GT+), 420 patients were BS+/GT-, and 177 were BS+/GT+. Our one-stop-shop check-up enabled us to diagnose 892 (72.9%) patients; 330 (27.0%) patients required additional examinations, such as mass spectrometry and/or a cardiac biopsy. This subset notably included 112 patients with amyloid light chain amyloidosis. More than 64% of the patients with transthyretin amyloidosis or another type of amyloidosis were diagnosed during the one-stop shop visit. Sensitivity and specificity of BS for transthyretin amyloidosis diagnosis was 99% and 96%, respectively. For amyloid light chain diagnosis, sensitivity and specificity were 100% and 76%, respectively, for GT and 54% and 100%, respectively, for SGB. Of 910 transthyretin genetic tests, 205 (17%) detected mutations., Conclusion: The results of our real-life cohort study confirmed the ability of a one-stop-shop approach with a modified Gillmore algorithm to diagnose cardiac amyloidosis and the interest of simultaneous testing for earlier diagnosis. The SGB has diagnostic value because it is easy, quick, and less invasive than a cardiac biopsy., (Copyright © 2022 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

The causal protein of amyloid light-chain (AL) amyloidosis is a monoclonal immunoglobulin free light chain (mFLC), which must be quantified in the serum for patient diagnosis and monitoring. Several manufacturers commercialize immunoassays that quantify total kappa (κ) and lambda (λ) FLC, but results can differ greatly between these tests. Here, we compared a recently developed enzyme-linked immunosorbent assay (ELISA) (Sebia) with N-Latex immunonephelometry (Siemens) in 96 patients diagnosed with AL amyloidosis (histologically confirmed) and 48 non-AL patients sent to our referral center for suspicion of cardiac amyloidosis. ELISA free-light chain difference (dFLC) were lower than N-Latex values, and agreement between methods was reduced in the case of involved λ FLC. Diagnosis sensitivity and specificity were >85% with both assays. A receiver operating characteristic analysis indicated that ELISA performances could be improved by using a higher value for the lower limit of the κ/λ ratio. We also assessed Freelite (The Binding Site) in a subgroup of these same AL patients, including 18 cases with normal κ/λ ratio by at least one assay. Only two patients had normal κ/λ ratio with all three assays. Overall, ELISA demonstrated slightly lower sensitivity than N-Latex but may be an alternative to nephelometry/turbidimetry in certain difficult cases., Competing Interests: Sebia (Lisses, France) provided financial support corresponding to the cost of the FLC tests dedicated to the study and performed the ELISAs. T D has received consultant fees and research grants from The Binding Site, AKCEA, ALNYLAM, GSK, PFIZER, PROTHENA and NEURIMMUNE. V A received consulting fees from Addmedica outside of the submitted work., (© 2022 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Heart transplantation in cardiac amyloidosis (CA) patients is possible and generally considered for transplantation if other organs are not affected. In this study, we aimed to describe and assess outcome in patients following heart transplantations at our CA referral center., Methods: We assessed all CA patients that had heart transplantations at our center between 2005 and 2018. Patients with New York Heart Association status 3 out of 4, with poor short-term prognosis due to heart failure, despite treatment, and without multiple myeloma, systemic disease, severe neuropathic/digestive comorbidities, cancer, or worsening infections were eligible for transplantation. Hearts were transplanted by bicaval technique. Standard induction and immunosuppressive therapies were used. Survival outcome of CA patients after transplantation was compared with recipients with nonamyloid pathologies in France., Results: Between 2005 and 2018, 23 CA patients had heart transplants: 17 (74%) had light chain (light chain amyloidosis [AL]) and 6 (26%) had hereditary transthyretin (hereditary transthyretin amyloidosis [ATTRv]) CA. Also, 13 (57%) were male, and the mean age at diagnosis was 56.5 y (range, 47.7-62.8). Among AL patients, 13 had heart-only and 5 had heart-kidney transplantations. Among ATTRv patients, 1 had heart-only and 5 had heart-liver transplantations. The 1-y survival rate after transplantation was 78%, 70% with AL, and 100% with ATTRv. At 2 y, 74% were alive: 65% with AL and 100% with ATTRv., Conclusion: After heart transplantation, French CA and nonamyloid patients have similar survival outcomes. Among CA patients, ATTRv patients have better prognosis than those with AL, possibly due to the combined heart-liver transplantation. Selected CA patients should be considered for heart transplantations., (Copyright © 2022 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Background: The three main cardiac amyloidosis (CA) types have different progression and prognosis. Little is known about the mode of death (MOD) which is commonly attributed to cardiovascular causes in CA. Improving MOD's knowledge could allow to adapt patient care., Objective: This retrospective study describes the MOD that occurred during long-term follow-up in CA patients in light-chain (AL), transthyretin hereditary (ATTRv) or wild-type (ATTRwt)., Material and Methods: Patients referred to and cared for, at the French referral centre for CA, Henri Mondor Hospital, Créteil between 2010 and 2016 were included. Clinical information surrounding patient deaths were investigated and centrally evaluated by two blinded clinical committees which classified MOD as cardiovascular, non-cardiovascular or unknown and sub-classified it depending on its subtype., Results: From the 566 patients included, 187 had AL, 206 ATTRv and 173 ATTRwt. During the 864 patient-year follow-up, 160 (28%) deaths occurred, with median survival time of 17.3 months (interquartile range 5.1-35.4). The most frequent MOD was cardiovascular (64%) of which worsening heart failure occurred most frequently and for which, 69% were of AL subtype, 79% ATTRv and 76% ATTRwt. Sudden death also occurred more frequently in AL subtype accounting for 29% of AL deaths. Non-cardiovascular MOD occurred in 26% of patients overall. Among these, infection was the most common non-cardiovascular MOD in any type of CA (80%)., Conclusions: Mortality is high during natural course of CA and differs between subtypes. The main MOD were worsening heart failure, sudden death and infection, opening room to optimise management.

Aims: Iron deficiency (ID) is common in patient with chronic heart failure (HF) and has been widely studied. In contrast, data concerning ID in cardiac amyloidosis (CA) are limited. Amyloidosis is a severe and fatal systemic disease, characterized by an accumulation of amyloid fibrils in various tissues/organs, including nerves, kidneys, gastrointestinal tract, and heart. Amyloid deposits in the heart eventually cause HF. The main subtypes of CA are light chain (AL), hereditary transthyretin (ATTRv), and wild-type transthyretin (ATTRwt). We performed this study to determine the prevalence, clinical outcome (all-cause mortality), and determinants of ID among the three main subtypes of CA., Methods and Results: Iron deficiency status were analysed in 816 CA patients enrolled at the French Referral Centre for Cardiac Amyloidosis: 271 (33%) had AL, 164 (20%) ATTRv, and 381 (47%) ATTRwt. ID affected 49% of CA patients, 45% with AL, 58% with ATTRv, and 48% with ATTRwt. We identified ATTR status (ATTRv P = 0.003, ATTRwt P = 0.037), diabetes (P = 0.003), aspirin treatment (P = 0.009), haemoglobin levels (P = 0.006), and altered global longitudinal strain (P = 0.02) as independent ID determinants. There is no difference in all-cause mortality considering ID status., Conclusions: Iron deficiency is common in patients with CA, irrespective of the subtype. Patients seem more likely to have ID if diagnosed with ATTR, if diabetic, and/or treated with aspirin. In CA, the benefit of intravenous iron therapy, for ID, on morbidity and mortality needs further study., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Cardiac amyloidosis (CA) has a poor prognosis which is aggravated by diagnostic delay. Amyloidosis extracardiac and cardiac events (AECE and ACE) may help improve CA diagnosis and typing. The aim of this study was to compare AECE and ACE between different CA types and assess their relationship with survival., Methods and Results: This retrospective cohort study conducted in France from June 2008 to May 2019, at the Henry Mondor Hospital. This cohort included 983 patients with CA. Mean age at inclusion was 73.1 ± 11.4 years, 726 (75.1%) were male and the mean body mass index was 24.5 ± 4.1 kg/m 2 . Among them, 321 had immunoglobulin light chain (AL) amyloidosis, 434 had wild-type transthyretin (ATTRwt), and 212 had hereditary transthyretin (ATTRv). The first AECE and/or ACE occurred at a mean age of 63 ± 11 years for AL and ATTRv, and 70 ± 12 years for ATTRwt (P < 0.01). The median (Q1-Q3) delay between declaration of the first events and diagnosis varied from 11.1 (5.9; 34.8) months for AL to 92.2 (39.0; 174.7) months for ATTRwt (P < 0.01). The nature of the onset of AECE or ACE varied based on amyloidosis type, heart failure symptoms for AL (26%) and integumentary symptoms for ATTRv with cardiologic or mixed phenotype (39%) and ATTRwt (42%). In AL and ATTRwt, a short delay between the onset of the first AECE or ACE and diagnosis was associated with reduced survival rate (log-rank test P-value <0.01)., Conclusions: This study highlights the impact of amyloidosis type and evolution on diagnostic delay and on prognosis. Physicians must be aware and vigilant in front of extracardiac and cardiac events to considerably improve early diagnosis of amyloidosis., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Cardiac amyloidosis (CA) is a set of amyloid diseases with usually predominant cardiac symptoms, including light-chain amyloidosis (AL), hereditary variant transthyretin amyloidosis (ATTRv), and wild-type transthyretin amyloidosis (ATTRwt). CA are characterized by high heterogeneity in phenotypes leading to diagnosis delay and worsened outcomes., Objectives: The authors used clustering analysis to identify typical clinical profiles in a large population of patients with suspected CA., Methods: Data were collected from the French Referral Center for Cardiac Amyloidosis database (Hôpital Henri Mondor, Créteil), including 1,394 patients with suspected CA between 2010 and 2018: 345 (25%) had a diagnosis of AL, 263 (19%) ATTRv, 402 (29%) ATTRwt, and 384 (28%) no amyloidosis. Based on comprehensive clinicobiological phenotyping, unsupervised clustering analyses were performed by artificial neural network-based self-organizing maps to identify patient profiles (clusters) with similar characteristics, independent of the final diagnosis and prognosis., Results: Mean age and left ventricular ejection fraction were 72 ± 13 years and 52% ± 13%, respectively. The authors identified 7 clusters of patients with contrasting profiles and prognosis. AL patients were distinctively located within a typical cluster; ATTRv patients were distributed across 4 clusters with varying clinical presentations, 1 of which overlapped with patients without amyloidosis; interestingly, ATTRwt patients spread across 3 distinct clusters with contrasting risk factors, biological profiles, and prognosis., Conclusions: Clustering analysis identified 7 clinical profiles with varying characteristics, prognosis, and associations with diagnosis. Especially in patients with ATTRwt, these results suggest key areas to improve amyloidosis diagnosis and stratify prognosis depending on associated risk factors., Competing Interests: Funding Support and Author Disclosures Dr Bonnefous is supported by a PhD grant from GlaxoSmithKline. Dr Oghina has received honoraria from Pfizer. Dr Damy has received research and/or consultant fees from GlaxoSmithKline, Alnylam, Pfizer, Prothena, Ionis, Akcea, and Janssen. Dr Audureau has received consultant fees from GBT and Hemanext. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: We assesse the evolution and prognostic value of N-terminal pro-brain natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (cTnT-HS) in transthyretin amyloid cardiomyopathy (ATTR-CA) before and after tafamidis treatment., Methods and Results: 454 ATTR-CA patients without tafamidis (Cohort A) and 248 ATTR-CA with tafamidis (Cohort B) were enrolled. Event-free survival (EFS) events were death, heart transplant, or acute heart failure. In Cohort A, 27% of patients maintained NT-proBNP < 3000 ng/L and 14% cTnT-HS < 50 ng/L at 12 months relative to baseline levels. In Cohort B, the proportions were 49% and 29%, respectively. In Cohort A, among the 333 patients without an increased NT-proBNP > 50% relative to baseline EFS was extended compared to the 121 patients with an increased NT-proBNP > 50% (HR: 0.75 [0.57; 0.98]; p = 0.032). In Cohort A, baseline NT-proBNP > 3000 ng/L and cTnT-HS > 50 ng/L and a relative increase of NT-proBNP > 50% during follow-up were independent prognostic factors of EFS. The slopes of logs NT-proBNP and cTnT-HS increased with time before and stabilized after tafamidis., Conclusion: ATTR-CA patients with increasing NT-proBNP had an increased risk of EFS. Tafamidis stabilize NT-proBNP and cTnT-HS increasing, even if initial NT-proBNP levels were >3000 ng/L. Thus suggesting that all patients, irrespective of baseline NT-proBNP levels, may benefit from tafamidis.

Background: Cardiac light chain amyloidosis (AL-CA) patients often die within three months of starting chemotherapy. Chemotherapy for non-immunoglobulin M gammopathy with AL-CA frequently includes bortezomib (Bor), cyclophosphamide (Cy), and dexamethasone (D). We previously reported that NT-ProBNP levels can double within 24h of dexamethasone administration, suggesting a deleterious impact on cardiac function. In this study, we evaluate the role of dexamethasone in early cardiovascular mortality during treatment., Methods and Findings: We retrospectively assessed 100 de novo cardiac AL patients (62% male, mean age 68 years) treated at our institute between 2009 and 2018 following three chemotherapy regimens: CyBorDComb (all initiated on day 1; 34 patients), DCyBorSeq (D, day 1; Cy, day 8; Bor, day 15; 17 patients), and CyBorDSeq (Cy, day 1; Bor, day 8; D, day 15; 49 patients). The primary endpoint was cardiovascular mortality and cardiac transplantation at days 22 and 455. At day 22, mortality was 20.6% with CyBorDComb, 23.5% with DCyBorSeq, and 0% with CyBorDSeq (p = 0.003). At day 455, mortality was not significantly different between regimens (p = 0.195). Acute toxicity of dexamethasone was evaluated on myocardial function using a rat model of isolated perfused heart. Administration of dexamethasone induced a decrease in left ventricular myocardium contractility and relaxation (p<0.05), supporting a potential negative inotropic effect of dexamethasone in AL-CA patients with severe cardiac involvement., Conclusion: Delaying dexamethasone during the first chemotherapy cycle reduces the number of early deaths without extending survival. It is clear that dexamethasone is beneficial in the long-term treatment of patients with AL-CA. However, the initial introduction of dexamethasone during treatment is critical, but may be associated with early cardiac deaths in severe CA. Thus, it is important to consider the dosage and timing of dexamethasone introduction on a patient-severity basis. The impact of dexamethasone in the treatment of AL-CA needs further investigation., Competing Interests: Pr Vincent Audard received consulting fees from Addmedica not related to the submitted work. Dr Silvia Oghina reported personal fees from Pfizer, outside of the submitted work. Pr Thibaud Damy received grant and/or consulting fees from PFIZER, AKCEA, ALNYLAM, PROTHENA, and JANSSEN outside the submitted work. The other authors declared no conflict of interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Aims: The prevalence of autonomic neuropathy (AN) is high in patients with hereditary transthyretin amyloidosis but remains unknown in transthyretin wild-type cardiac amyloidosis (ATTRwt-CA). This study aimed to determine the prevalence of AN in patients with ATTRwt-CA using Sudoscan®, a non-invasive method used to provide evidence of AN in clinical practice and based on measurement of electrochemical skin conductance at the hands and feet (fESC)., Methods and Results: A series of 62 non-diabetic patients with ATTRwt-CA was prospectively included over 2 years and compared with healthy elderly subjects, matched by age, gender, and body mass index. The presence of AN was defined as electrochemical skin conductance at the hands <60 μS and/or fESC <70 μS, and conductances were analysed according to clinical, biological, and echocardiographic data. Mean fESC was significantly lower in patients with ATTRwt-CA compared with elderly controls: 68.3 (64.1-72.5) vs. 76.9 (75.6-78.1) μS (P < 0.0001), respectively. Prevalence of fESC <70 μS was higher in ATTRwt-CA patients than in controls: 48.4% vs. 19.9%, P < 0.05. Univariate analysis showed that fESC, N-terminal pro-B-type natriuretic peptide, creatinine plasma levels, and echocardiographic global longitudinal strain were associated with decompensated cardiac failure and death. Multivariate analysis revealed that fESC was an independent prognostic factor, and Kaplan-Meier estimator evidenced a greater occurrence of cardiac decompensation and death in patients with fESC <70 μS, P = 0.046., Conclusions: Reduced fESC was observed in almost 50% of patients with ATTRwt-CA and was associated with a worse prognosis. Sudoscan® could easily be used to screen ATTRwt-CA patients for the presence of AN and identify patients at higher risk for a poor outcome., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Heart failure with preserved ejection fraction (HFpEF) is an increasingly diagnosed condition whose failure to respond to new drugs effective in heart failure with reduced ejection fraction is of great concern. HFpEF is an incompletely understood and markedly heterogeneous syndrome, but cardiac amyloidosis is increasingly recognized as one of its various causes. The specific hemodynamic and pathophysiological features of cardiac amyloidosis result in poor tolerance of heart failure medications and in worse outcomes compared with other causes. Until recently, patients considered for HFpEF trials were not routinely screened for cardiac amyloidosis. This review examines how real-world patients with cardiac amyloidosis met inclusion criteria for 8 major HFpEF clinical trials, including the recent PARAGON (Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction) trial. This review discusses how the presence in the trial populations of a subset of patients with cardiac amyloidosis might contribute to explain the absence of efficacy of medications for HFpEF in trials so far. A multistep screening strategy is suggested in which patients with red flags for cardiac amyloidosis undergo both a light chain assay and technetium-labeled cardiac scintigraphy (technetium-labeled cardiac scintigraphy scan), which, when negative, rule out cardiac amyloidosis. Using this strategy would allow the testing of new medications for HFpEF in populations containing no patients with cardiac amyloidosis, thus potentially increasing the likelihood of showing therapeutic efficacy, and finally making some effective treatment available., Competing Interests: Funding Support and Author Disclosures This work was supported by the nonprofit organization AREMCAR (Association pour la Recherche et l’Étude des Maladies Cardiovasculaires). Dr. Oghina has received honoraria from Pfizer. Dr. Bougouin has received honoraria from Withings. Dr. Cohen-Solal has received fees from Novartis, Servier, Merck Sharp and Dohme, AstraZeneca, Vifor Pharma, Amgen, CVRX, Menarini, Roche Diagnostics, Abbott, Bristol-Myers Squibb. Dr. Damy has received research support and honoraria from Alnylam, Pfizer, GlaxoSmithKline, and Neurimmune. Dr. Bodez has received honoraria from Alnylam and Vifor Pharma. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: Hereditary (ATTRv) and wild-type (ATTRwt) transthyretin amyloidosis are severe and fatal systemic diseases, characterised by amyloid fibrillar accumulation principally in the heart or peripheral nerves (or both). Since 2012, tafamidis has been used in France to treat patients with ATTRv with neuropathy (alone or combined with cardiomyopathy). Recently, the Phase III ATTR-ACT trial showed that tafamidis decreased the relative risk of mortality in ATTR amyloidosis with cardiomyopathy. The aims of this study were to assess the clinical characteristics of ATTR amyloidosis in a real-life population in comparison to the population included in the ATTR-ACT trial and to assess the impact of tafamidis treatment on major cardiovascular outcome (MCO)-free survival time without cardiac decompensation, heart transplant, or death., Methods and Results: From June 2008 to November 2018, 648 patients with ATTR amyloidosis (423 ATTRwt and 225 ATTRv) consecutively referred to the French Referral Center for cardiac amyloidosis were included. A total of 467 (72%) patients matched the inclusion criteria of the ATTR-ACT trial. For the 631 patients with cardiomyopathy, tafamidis treatment was associated with a longer median MCO-free survival time (n = 98): 1565 (1010-2400) days vs. 771 (686-895) days without treatment (log-rank P < 0.001). This association was confirmed after considering confounding factors (age at inclusion, N-terminal pro-B-type natriuretic peptide and amyloidosis type) with a propensity score (hazard ratio 0.546; P = 0.0132)., Conclusion: In a large cohort of ATTRwt and ATTRv patients, representative of the inclusion criteria of the ATTR-ACT trial, the present results show an association between tafamidis treatment and a lower occurrence of cardiovascular outcomes in a real-life population., (© 2020 European Society of Cardiology.)