Diagnostic Value of Extracellular Volume Quantification and Myocardial Perfusion Analysis at CT in Cardiac Amyloidosis.

Background CT can provide information regarding myocardial perfusion and expansion of the extracellular space, which is relevant to patients with cardiac amyloidosis (CA). Purpose To evaluate the role of CT in the diagnosis and prognosis of CA. Materials and Methods In this prospective study (Commission National de l'Informatique et des Libertés registration no. 1431858), participants with CA, participants with nonamyloid cardiac hypertrophy (NACH), and participants without hypertrophy were included between April 2017 and December 2018. The confirmed diagnosis of CA was determined according to established criteria (ie, proven with positive bone scintigraphy or endomyocardial biopsy). All participants were imaged with dynamic CT perfusion imaging at whole-heart cardiac CT. Extracellular volume measured at CT and myocardial perfusion parameters calculated on CT perfusion maps were compared among different participant groups. Differences between continuous data were tested using the unpaired t test, Mann-Whitney rank-sum test, or the Kruskal-Wallis test. Results A total of 84 participants with CA, 43 participants with NACH, and 33 participants without hypertrophy were included. Participants with CA exhibited a higher value of extracellular volume measured at CT (mean, 54.7% ± 9.7 [standard deviation]) than participants with NACH (mean, 34.6% ± 9.1; P < .001) and participants without hypertrophy (mean, 35.9% ± 9.9; P = .001). Mean myocardial blood volume and mean myocardial blood flow were lower in participants with CA (mean myocardial blood volume: 4.05 mL/100 g of myocardium ± 0.80; mean myocardial blood flow: 73.2 mL/100 g of myocardium per minute ± 25.7) compared to participants with NACH (mean myocardial blood volume: 5.38 mL/100 g of myocardium ± 1.20, P < .001; mean myocardial blood flow: 89.6 mL/100 g of myocardium per minute ± 31.3, P = .007) and participants without hypertrophy (mean myocardial blood volume: 5.68 mL/100 g of myocardium ± 1.05; mean myocardial blood flow: 106.3 mL/100 g of myocardium per minute ± 29.8; P < .001 for both). Extracellular volume measured at CT (hazard ratio >0.56 vs ≤0.56 = 4.2 [95% CI: 1.4, 11.8]), mean slope (hazard ratio ≤3.0 sec-1 vs >3.0 sec-1 = 0.2 [95% CI: 0.1, 0.8]), and time to peak (hazard ratio >20 seconds vs ≤20 seconds = 11.6 [95% CI: 1.3, 101.6]) were predictive of mortality in participants with CA. Conclusion Participants with cardiac amyloidosis exhibited an increase in extracellular volume at CT and abnormal CT perfusion parameters. Extracellular volume and several perfusion parameters were predictive of mortality. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Zimmerman in this issue.

AA amyloidosis complicating monoclonal gammopathies, an unusual feature validating the concept of "monoclonal gammopathy of inflammatory significance"?

INTRODUCTION: AL amyloidosis is caused by the proliferation of an immunoglobulin-secreting B cell clone. AA amyloidosis is a rare complication of chronic inflammation. However, some patients present with diseases combining monoclonal immunoglobulin production and chronic inflammation. The aim of this work was to describe cases of AA amyloidosis associated with monoclonal gammopathies. PATIENTS AND METHODS: We reviewed all patients reported in French national amyloid centres presenting with AA amyloidosis and monoclonal gammopathy and performed a literature review. The quality of AA amyloidosis diagnosis and the causal relationship with monoclonal gammopathy were assessed. RESULTS: In total, four patients from our centres and eight from the literature fulfilled the inclusion criteria. The haematological disorders presenting with monoclonal gammopathy were as follows: Waldenström macroglobulinaemia (n = 8), Schnitzler syndrome (n = 2), multiple myeloma (n = 1) and monoclonal gammopathy of undetermined significance (n = 1). Treatment strategies varied among the cases, with the treatment of the haematological disorder in 4 and anti-inflammatory treatment in 2. CONCLUSION: Monoclonal gammopathies might be a rare and poorly known cause of AA amyloidosis. Such monoclonal gammopathies could be named "monoclonal gammopathies of inflammatory significance."

[Cardiac amyloidosis]. / Les amyloses cardiaques.

Different types of amyloid deposits involve the heart. Transthyretin and light chain amyloidosis are the most frequent. Diagnostic performance, typing and treatments have improved in the last decade, and prognosis of cardiac amyloidosis is now significantly better thanks to targeted therapies. In this article, we will describe the clinical manifestations of cardiac amyloidosis, the diagnostic approach and detail the characteristics and specific treatments of the most frequent types of cardiac amyloidosis. We will focus on the histopathological aspects, especially on the importance of amyloid typing.

Extracardiac soft tissue uptake, evidenced on early 99mTc-HMDP SPECT/CT, helps typing cardiac amyloidosis and demonstrates high prognostic value.

PURPOSE: Increased cardiac uptake (CU) on early-phase 99mTc-HMDP scintigraphy has demonstrated diagnostic and prognostic values in amyloid transthyretin (ATTR) cardiac amyloidosis (CA). Extracardiac uptake (ECU) has been poorly studied. We assessed the clinical value of ECU, in combination with CU, on 99mTc-HMDP scintigraphy using a novel Methodological Amyloidosis Diagnostic Index (MADI). METHODS: We reviewed all patients referred for suspicion of CA, who underwent 99mTc-HMDP scintigraphy over an 8-year period. ECU, CU, and MADI were determined: MADI0 = neither ECU or CU, MADI1 = ECU alone, MADI2 = CU alone, and MADI3 = ECU + CU. RESULTS: Of 308 eligible patients, 247 had CA, including 75 ATTRv, 107 ATTRwt, and 65 light-chain (AL), while 61 had another cardiopathy (controls). ECU was observed in 29% of CA and 3% of controls. Most frequent sites of ECU were pleuropulmonary (16% of CA, 3% of controls) followed by the digestive tract and subcutaneous tissues. The liver and spleen ECU was only observed in AL-CA (n = 8). CU was only observed in CA patients (n = 187), of whom 182 had ATTR-CA vs. 5 AL-CA, P < 0.001. MADI0 was only observed in controls (97%) and in AL-CA (60%). MADI1 was mainly observed in AL-CA (positive predictive value, PPV = 91%) while MADI2/3 were more frequent in ATTR-CA (PPV = 97%), P < 0.0001. MADI > 0 vs. MADI0 in AL and MADI3 vs. MADI2 in ATTR were associated with a worse prognosis (P = 0.03 and P = 0.002, respectively). CONCLUSIONS: ECU combined with CU demonstrates high diagnostic and prognostic values in CA patients. MADI seems an easy and reliable score in clinical practice.

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

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

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

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

Frailty in heart failure according to the presence or absence of wild-type transthyretin cardiac amyloidosis.

AIMS: Wild-type transthyretin cardiac amyloidosis (ATTRwt CA) is a common, underdiagnosed cause of heart failure (HF) in the elderly. Concurrent extracardiac amyloid infiltration might be responsible for a specific frailty phenotype. This study aims to compare the prevalence and characteristics of frailty parameters in HF patients, with or without ATTRwt CA. METHODS: In a comparative cross-sectional study, we prospectively included consecutive HF patients with or without ATTRwt CA (the HF + ATTRwt+ and HF + ATTRwt- groups, respectively) between April 2018 and April 2021. Logistic regression models were used to compare the groups with regard to frailty as assessed using multidimensional geriatric tools. RESULTS: We included 123 patients (68 HF + ATTRwt+ and 55 HF + ATTRwt-). The mean age was 80.9 (standard deviation 6.3) years, 87% were male, 34% had left ventricular systolic dysfunction and 34% were New York Heart Association (NYHA) III. Relative to the HF + ATTRwt- group, patients in the HF + ATTRwt+ group were more likely to have shrinking [odds ratios = 2.9 (95% confidence interval, 1.1 to 1.7), P = 0.03], balance disorders [1.8 (1.1 to 2.8), P = 0.02], memory complaints [2.5, (1.0 to 5.9), P = 0.05] and overactive bladder [1.5 (1.1 to 2.2), P = 0.03], independently of age, sex, NYHA class and diabetes status. The proportion of very frail patients was higher (albeit not significantly) in the HF + ATTRwt+ group than in the HF + ATTRwt- group [2.4 (0.9 to 6.9), P = 0.10]. CONCLUSIONS: ATTRwt CA is associated with a specific frailty phenotype. Patients with ATTRwt CA should be screened for frailty and managed collaboratively by cardiologists and geriatricians, with a view to improving quality of life.

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

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

Improving genetic testing pathways for transthyretin amyloidosis in France: challenges and strategies.

Transthyretin amyloidosis (ATTR) is a severe and rare disease characterized by the progressive deposition of misfolded transthyretin proteins, causing irreversible organ damage. Transthyretin amyloidosis can present as a hereditary ATTR or acquired wild-type ATTR form. Genetic testing is critical for determining a hereditary predisposition and subsequently initiating appropriate family screening. In France, strict regulations govern genetic testing that aim to protect patients and their families affected by hereditary diseases such as ATTR. However, challenges persist in establishing an effective genetic testing pathway. A multidisciplinary group of French experts convened to discuss the challenges associated with an ATTR genetic diagnosis and to propose improvement strategies. Key challenges include the lack of pathway standardization, communication gaps between healthcare professionals (HCPs) and patients, and difficulties in complying with regulatory requirements. Concerns about patient data safety and outsourced testing quality further complicate matters. Proposed strategies included the development of stakeholder mapping tools for HCPs and patients, educational programs to improve literacy on genetic testing regulations, increase disease awareness among medical geneticists and genetic counselors, and strengthening HCP-patient communication through educational materials. These initiatives aim to streamline the genetic testing pathway, enhance compliance with regulations, and ultimately provide optimal support for patients and families with ATTR.

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

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

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

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

Real-Life Evaluation of an Algorithm for the Diagnosis of Cardiac Amyloidosis.

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.

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

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

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

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

Electrical cardioversion of atrial arrhythmias with cardiac amyloidosis in the era of direct oral anticogulants.

AIMS: Atrial fibrillation (AF)/atrial flutter is common during cardiac amyloidosis (CA). Electrical cardioversion (EC) is a strategy to restore sinus rhythm (SR). However, left atrial thrombus (LAT) represents a contraindication for EC. CA patients with AF/atrial flutter have a high prevalence of LAT. We aimed to evaluate EC characteristics, LAT prevalence and risk factors, and AF/atrial flutter outcome in CA patients undergoing EC, predominantly treated with direct oral anticoagulants (DOACs). METHODS AND RESULTS: All patients with CA and AF/atrial flutter referred for the first time to our national referral centre of amyloidosis for EC from June 2017 to February 2021 were included in this study. In total, 66 patients (median age 74.5 [70;80.75] years, 67% male) were included with anticoagulation consisted of DOAC in 74% of cases. All patients underwent cardiac imaging before EC to rule out LAT. EC was cancelled due to LAT in 14% of cases. Complete thrombus resolution was observed in only 17% of cases. The two independent parameters associated with LAT were creatinine [hazard ratio (HR) = 1.01; confidence interval (CI) = 1.00-1.03, P = 0.036] and the use of antiplatelet agents (HR = 13.47; CI = 1.85-98.02). EC acute success rate was 88%, and we observed no complication after EC. With 64% of patients under amiodarone, AF/atrial flutter recurrence rate following EC was 51% after a mean follow-up of 30 ± 27 months. CONCLUSIONS: Left atrial thrombus was observed in 14% of CA patients listed for EC and mainly treated with DOAC. The acute EC success rate was high with no complication. The long-term EC success rate was acceptable (49%).

Prevalence and determinants of iron deficiency in cardiac amyloidosis.

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.

Evaluation of a new ELISA assay for monoclonal free-light chain detection in patients with cardiac amyloidosis.

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.

Describing mode of death in three major cardiac amyloidosis subtypes to improve management and survival.

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.

Prognosis of Transthyretin Cardiac Amyloidosis Without Heart Failure Symptoms.

Background: Transthyretin amyloid cardiomyopathy (ATTR-CM) is increasingly recognized as a treatable cause of heart failure (HF). Advances in diagnosis and therapy have increased the number of patients diagnosed at early stages, but prognostic data on patients without HF symptoms are lacking. Moreover, it is unknown whether asymptomatic patients benefit from early initiation of transthyretin (TTR) stabilizers. Objectives: The aim of this study was to describe the natural history and prognosis of ATTR-CM in patients without HF symptoms. Methods: Clinical characteristics and outcomes of patients with ATTR-CM without HF symptoms were retrospectively collected at 6 international amyloidosis centers. Results: A total of 118 patients (78.8% men, median age 66 years [IQR: 53.8-75 years], 68 [57.6%] with variant transthyretin amyloidosis, mean left ventricular ejection fraction 60.5% ± 9.9%, mean left ventricular wall thickness 15.4 ± 3.1 mm, and 53 [45%] treated with TTR stabilizers at baseline or during follow-up) were included. During a median follow-up period of 3.7 years (IQR: 1-6 years), 38 patients developed HF symptoms (23 New York Heart Association functional class II and 14 functional class III or IV), 32 died, and 2 required cardiac transplantation. Additionally, 20 patients received pacemakers, 13 developed AF, and 1 had a stroke. Overall survival was 96.5% (95% CI: 91%-99%), 90.4% (95% CI: 82%-95%), and 82% (95% CI: 71%-89%) at 1, 3, and 5 years, respectively. Treatment with TTR stabilizers was associated with improved survival (HR: 0.31; 95% CI: 0.12-0.82; P = 0.019) and remained significant after adjusting for sex, age, ATTR-CM type, and estimated glomerular filtration rate (HR: 0.18; 95% CI: 0.06-0.55; P = 0.002). Conclusions: After a median follow-up period of 3.7 years, 1 in 3 patients with asymptomatic ATTR-CM developed HF symptoms, and nearly as many died or required cardiac transplantation. Treatment with TTR stabilizers was associated with improved prognosis.