Liver stiffness as a prognostic parameter and tool for risk stratification in advanced cardiac transthyretin amyloidosis.

BACKGROUND: In light of increasing therapeutic options, risk stratification of advanced cardiac transthyretin amyloidosis (ATTR-CA) is gaining clinical importance to avoid ineffective treatments. Liver stiffness as a marker of hypervolemia and hepatic congestion might predict mortality in advanced ATTR-CA and allow to identify patients at highest risk. METHODS: Proven ATTR-CA patients underwent repeated vibration-controlled transient elastography (VTCE) and standardized serial workup within the local amyloidosis cohort study AmyKoS. Spearman correlation analyses and Cox regressions were performed to evaluate the prognostic value. RESULTS: 41 patients with ATTR-CA were included with median age of 76.6 (55.1-89.1) years, of which 90.2% were male and > 92% wild-type ATTR-CA. In total, 85 VCTE examinations were performed. Median follow-up was 43.7 (2.4-75.6) months; 26.8% of the patients died. At the first clinical evaluation, median left ventricular (LV) absolute global longitudinal strain (GLS) was 11.4 (5.2-19.0) % and median liver stiffness was 6.3 (2.4-22.9) kPa, both significantly correlated with mortality. NT-proBNP possessed statistically significant predictive power in ATTR-CA with more preserved LV function (absolute GLS ≥ 10), whereas stiffness seemed to be more discriminative for ATTR-CA with absolute GLS < 10. The use of alternative congestion surrogates such as liver vein dilation and tricuspid regurgitation peak velocity (tr-vmax) showed congruent results. CONCLUSION: Liver stiffness shows prognostic value regarding all-cause mortality and allows risk stratification in advanced ATTR-CA, particularly in those with markedly impaired longitudinal LV function. These results are transferable to other congestion surrogates.

[99mTc]Tc-hydroxydiphosphonate uptake in soft tissue is associated with amyloid load in subcutaneous abdominal fat tissue and mortality in wild-type transthyretin amyloidosis patients.

PURPOSE: Bone scintigraphy is key to non-invasively diagnosing wild-type transthyretin (ATTRwt) amyloidosis, and is mainly used to assess cardiac radiotracer uptake. However, extracardiac radiotracer uptake is also observed. We investigated whether intensity of soft tissue radiotracer uptake is associated with amyloid load in subcutaneous abdominal fat tissue and with mortality. METHODS: This prospective cohort study included 94 ATTRwt amyloidosis patients and 26 amyloid-negative heart failure controls who underwent whole-body [99mTc]Tc-hydroxydiphosphonate scintigraphy. Site-to-background ratios were calculated for heart, elbows, subcutaneous tissue, shoulders and wrists on anterior planar bone scintigraphy images using rib and whole-body radiotracer uptake as background. Fat tissue aspirates were stained with Congo red to grade amyloid load. Site-to-rib ratios were compared between ATTRwt amyloidosis patients and controls, and associations of site-to-background ratio with Congo red score and all-cause mortality were studied. RESULTS: ATTRwt amyloidosis patients had higher soft tissue-to-rib, heart-to-rib and heart-to-whole body ratios compared with controls. The intensity of soft tissue uptake was positively associated with amyloid load in fat tissue in ATTRwt amyloidosis patients. Estimated glomerular filtration rate, N-terminal brain natriuretic propeptide, high-sensitivity cardiac troponin T (hs-cTnT), and the prognostic Mayo and NAC staging system were associated with all-cause mortality in univariable models. Soft tissue/rib ratio, hs-cTnT and the prognostic staging systems were the only two variables that were independently associated withall-cause mortality. CONCLUSION: Soft tissue radiotracer uptake on bone scintigraphy in ATTRwt amyloidosis patients is positively associated with amyloid load in abdominal fat tissue and is independently associated with mortality.

Connective tissue amyloidosis in patients referred for orthopedic surgery. CONNECT-AMY study. / Amiloidosis del tejido conectivo en pacientes referidos a cirugía ortopédica. Estudio CONNECT-AMY.

INTRODUCTION AND OBJECTIVE: Clinical manifestations secondary to amyloid deposition in connective tissue may allow early detection of amyloidosis. We sought to identify the prevalence of connective tissue amyloidosis in patients undergoing orthopedic surgery and evaluate for cardiac involvement. MATERIAL AND METHODS: Descriptive cross-sectional study that included patients >50 years referred for orthopedic surgery at our center. A sample of the affected connective tissue was taken during the intervention to evaluate the presence of amyloid material. Those with confirmed amyloidosis were further evaluated with complementary tests for cardiac involvement. RESULTS: Forty-eight patients were included. Mean age was 65.4 years and 41.7% were women. The most frequent surgery was supraspinatus tendon rupture (50%). Transthyretin amyloid deposits were detected in 2 patients (4.2%). The absence of variants in the protein gene established the diagnosis of ATTRwt in both cases. None of them presented cardiac involvement. CONCLUSIONS: In this study, 4.2% of patients referred for orthopedic surgery presented transthyretin amyloidosis in the affected connective tissue.

ELISA-4-amyloid: diagnostic accuracy of an ELISA panel for typing the four main types of systemic amyloidosis in subcutaneous abdominal fat tissue samples.

BACKGROUND: Reliable typing of amyloid is essential. Amyloid extraction from tissue enables immunochemical typing of the precursor protein using an enzyme-linked immunosorbent assay (ELISA). OBJECTIVE: To assess the diagnostic accuracy of a panel of ELISAs for typing the four main types (AA, ATTR, AL-kappa and AL-lambda amyloid). METHODS: From 1996 to 2023 subcutaneous abdominal fat tissue aspirates were obtained from 1339 amyloidosis patients and 868 controls. Amyloid was visually graded 0-4+ in Congo red-stained smears. Amyloid extracted from tissue by Guanidine was typed using a panel comprising four ELISAs. RESULTS: All amyloid protein concentrations in extracts correlated with amyloid grade in smears. Typing sensitivity was low (23.3%) in samples with grade 1+/2+ amyloid. Overall typing sensitivity of the panel was 81.6% for all easily visible amyloid (grade 3+/4+): high for AA (98.8%) and ATTR (96.8%) and fair for AL-kappa (66.7%) and AL-lambda (75.9). Overall typing specificity was 98.0% and the overall positive predictive value was 98.0%. CONCLUSIONS: We describe a highly specific ELISA panel for routine typing of the main amyloid types in fat tissue. Until more sensitive typing techniques will become generally available, typing easily visible amyloid in fat tissue using this ELISA panel is reliable, affordable and straightforward.

Incremental prognostic utility of congestion markers in cardiac transthyretin amyloidosis.

BACKGROUND/AIMS: Congestion is prognostically relevant in cardiac transthyretin amyloidosis (ATTR-CA), but whether congestion has an incremental prognostic value beyond the well-established, congestion-sensitive NT-proBNP is unknown. Therefore, we aimed to comparatively evaluate the prognostic utility of several congestion surrogates over NT-proBNP. METHODS: We estimated hazard ratios by Cox proportional hazards regressions with time-varying covariates from a panel data set of the local amyloidosis cohort study AmyKoS. Different models were compared by using chi(χ)2-statistics measuring overall model significance. RESULTS/CONCLUSION: 131 ATTR-CA patients (wild-type 84.0%, hereditary 6.9%, without genetic testing 9.2%; median age 78.7 (quartiles 73.3, 82.1) years; 85.5% male) with 566 observations across a median follow-up of 38.2 (30.6; 48.2) months were analyzed. 83.2% received disease-modifying treatment; 20.6% participated concurrently in placebo-controlled gene silencer trials. Information on congestion improved biomarker-driven risk stratification and identified patients at the highest risk. Echocardiographic congestion markers performed better than clinical findings and daily diuretic use/dosage. Relevant adjusters were daily diuretic dosage, disease-modifying treatment, eGFR, and right atrial volume. NT-proBNP and the tricuspid regurgitation peak velocity (tr-vmax) provided an easy-to-use stratification with overall model performance similar to NAC and Mayo staging systems. Further analyses are necessary for validation and to identify the optimal cut points of the congestion markers.

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.

Wild-Type Transthyretin Amyloidosis: A Prevalent and Underdiagnosed Cause of Heart Failure With Preserved Ejection Fraction.

Cardiac amyloidosis is an infiltrative disease characterized by the extracellular deposition of misfolded protein in the myocardium, leading to increased stiffness and an eventual restrictive cardiomyopathy. The slow onset of symptoms and overlap with other cardiomyopathies make prompt diagnosis a challenge. Clinicians should be alerted and include amyloidosis in their differential diagnosis, particularly in patients with heart failure with preserved ejection fraction, unexplained left ventricle hypertrophy, particularly in those shown intolerance to previous antihypertensive medication, and early orthopedic manifestations of the disease such as carpal tunnel syndrome and spinal stenosis. The workup requires the exclusion of monoclonal gammopathies and technetium-99m pyrophosphate nuclear scintigraphy (99mTc-PYP) studies with single-photon emission computerized tomography (SPECT) imaging. Several therapies are now available and can prolong life with significantly improved quality of life, particularly when the diagnosis of amyloidosis is made early. We present the case of a 77-year-old with a delayed diagnosis by five years to highlight the need for heightened clinical suspicion and an appropriate diagnostic algorithm for cardiac amyloidosis.

Anticoagulation in Atrial Fibrillation Associated With Cardiac Amyloidosis: A Narrative Review.

Cardiac amyloidosis (CA) involves the abnormal deposition and accumulation of amyloid proteins in the heart muscle. A hallmark of disease progression is declining heart function, which can lead to structural irregularities, arrhythmias, and ultimately heart failure. Atrial fibrillation (AF) is the most common arrhythmia that presents in CA patients, and this arrhythmia is significant because it can moderately increase the risk of patients developing intracardiac thrombi, thereby putting them at risk for thromboembolic events. The management of this complication entails the use of anticoagulants like vitamin K antagonists and direct oral anticoagulants to reduce the risk of thrombus formation. This article seeks to review AF in CA and the use of anticoagulation therapy for the management and reduction of thromboembolic risk. The major conclusions of this review are centered around the need for safe administration of anticoagulant therapy to CA patients, regardless of their CHA2DS2-VASc risk score. This review highlights the importance of taking a multidisciplinary or collaborative approach to CA treatment to ensure that all aspects of this multifaceted disease can be properly managed while minimizing adverse events like bleeding risk and drug-drug interactions.

Transthyretin Cardiac Amyloidosis in an Elderly Male With Heart Failure Intolerant to Guideline-Directed Medical Therapy.

Cardiac amyloidosis arises when there is a deposition of abnormal proteins, called amyloids, in the myocardium. It can manifest as overt heart failure, conduction abnormalities, atrial and ventricular arrhythmia, cardiomyopathy, and aortic stenosis. Two main types of proteins identified in cardiac amyloidosis are light-chain amyloid and transthyretin amyloid. Cardiac amyloidosis, although common, is an underdiagnosed cause of heart failure in many cases. A high index of suspicion is needed to make a diagnosis, given that symptoms are not specific. Early diagnosis and treatment of cardiac amyloidosis are associated with reduced morbidity and improved survival. We present a case of a 73-year-old African American male with decompensated heart failure with reduced ejection fraction intolerant to guideline-directed medical therapy who was later found to have cardiac amyloidosis.

Impact of Anemia on Mortality and Morbidity in Transthyretin Amyloid Cardiomyopathy.

Anemia is prevalent in transthyretin amyloid cardiomyopathy (ATTR-CM), but its prognostic significance remains uncertain because of conflicting data mainly in patients not receiving disease-modifying therapy. Additionally, the effect of anemia on morbidity in this population has not been studied. This retrospective study included 270 patients diagnosed with ATTR-CM, receiving disease-modifying treatment (tafamidis), of which 30% (n = 80) were anemic (defined as a hemoglobin level <13 g/100 ml for males and <12 g/100 ml for females according to the World Health Organization). At baseline, patients with anemia were on average older (mean age 79 vs 77 years), more likely to be female (21% vs 12%), and exhibited higher symptom severity based on the New York Heart Association class (42% in class III vs 27%) compared with those without anemia. Additionally, they had a worse Columbia score (mean score 3 vs 5) and Columbia stage (12% in late-stage vs 7.1%) than those without anemia. Kaplan-Meier analysis indicates that anemia was associated with a higher likelihood of mortality, all-cause, and cardiovascular (CV) hospitalizations (p <0.05). However, in the Cox regression analysis, after adjusting for baseline age, ATTR genotype, and Columbia score, anemia was only associated with a higher risk of all-cause hospitalizations (hazard ratio 1.9 (1.3 to 2.7), p <0.001) and CV-related hospitalizations (hazard ratio 1.9 (1.2 to 2.9), p = 0.006). In conclusion, this study indicates that anemic patients with ATTR-CM have higher risks of CV and all-cause hospitalizations compared with nonanemic ATTR-CM patients. Further research is needed to understand how treating anemia may improve outcomes in this high-risk patient population.

Response to therapy with tafamidis 61 mg in patients with cardiac transthyretin amyloidosis: real-world experience since approval.

AIMS: Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive disease that causes heart failure due to amyloid fibril deposition. Tafamidis was approved as the first causal treatment in 2020. We here report on real-world data in patients treated with tafamidis for at least 12 months according to the recently defined European Society for Cardiology (ESC) consensus criteria for disease progression. METHODS AND RESULTS: Three hundred and eight wildtype and 31 hereditary ATTR-CM patients were prospectively enrolled after first diagnosis of ATTR-CM and initiation of tafamidis 61 mg once daily treatment. After 12 months, significant deterioration in Karnofsky Index, estimated glomerular filtration rate (eGFR), N-terminal brain natriuretic peptide (NT-proBNP), septum thickness and left ventricular ejection fraction (LVEF) could be observed, significant disease progression was only detected in 25 patients (9%) using ESC consensus criteria. Mean survival time was 37 months with no differences between responders and non-responders. NT-proBNP was the only independent predictor for poor therapy response (p = .008). CONCLUSIONS: The majority of patients showed no significant disease progression according to the ESC consensus criteria after 12 months of therapy with tafamidis. However, at 12 months, treatment response based on the ESC consensus criteria was not associated with improved survival. Moreover, higher levels of NT-proBNP at diagnosis of ATTR-CM appears to predict poorer treatment response, confirming that timely initiation of therapy is advantageous.

Examining the Difficulties in Identifying and Handling Cardiac Amyloidosis; Acquiring Important Knowledge and Robust Treatment Methods.

Systemic amyloidosis is a rare protein misfolding and deposition condition that causes slow organ failure. Each of the more than 15 exclusive sorts of systemic amyloidosis, which encourage amyloid production and tissue deposition, is introduced by a unique precursor protein. Amyloidosis can affect various organs, including the heart, kidneys, liver, nerves, gastrointestinal tract, lungs, muscles, skin, and soft tissues. It can either be acquired or hereditary. Insidious and doubtful signs often cause a put-off in diagnosis. In the closing decade, noteworthy progressions have been made in the identity, prediction, and handling of amyloidosis. Shotgun proteomics based on mass spectrometry has revolutionized amyloid typing and enabled the identification of novel amyloid forms. It is critical to correctly identify the precursor protein implicated in amyloidosis because the kind of protein influences the proper treatment strategy. Cardiac amyloidosis is a disorder characterized by the systemic accumulation of amyloid protein in the myocardium's extracellular space, which causes a variety of symptoms. The buildup of amyloid aggregates precipitates myocardial thickening and stiffening, culminating in diastolic dysfunction and, in due course, heart failure. We examine every kind of systemic amyloidosis in this text to offer practitioners beneficial equipment for diagnosing and treating those unusual diseases. This review presents a comprehensive analysis of cardiac amyloidosis and consolidates current methods for screening, diagnosis, evaluation, and treatment alternatives.

Tafamidis therapy in transthyretin amyloid cardiomyopathy: a narrative review from clinical trials and real-world evidence.

BACKGROUND: Amyloidosis is a heterogeneous group of disorders caused by the extracellular deposition of insoluble misfolded proteins, leading to end-organ damage. Transthyretin amyloid cardiomyopathy (ATTR-CM) is a subtype in which a protein known as transthyretin accumulates within the heart tissue, progressively resulting in restrictive cardiomyopathy and heart failure. Due to the progressive nature of ATTR-CM, clinical management requires efficacious regimens to manage the debilitating condition and Tafamidis shows promising results in this regard. MAIN BODY: ATTR-CM poses a significant challenge due to its nature and limited therapeutic options. Tafamidis is a novel therapy designed to stabilize the transthyretin tetramers, inhibiting the formation of amyloid fibrils. It has emerged as a promising treatment and the only FDA-approved drug for ATTR-CM. Tafamidis' role in slowing disease progression and improving outcomes in patients with ATTR-CM has been demonstrated in the major randomized control trial ATTR-ACT with promising open-label extension studies, some still ongoing. Additionally, real-world evidence supports its use in clinical practice, showing its role in reducing morbidity and mortality associated with this condition. Clinical evidence shows its efficacy in improving symptoms and cardiac function in patients. Case studies also reveal significant benefits to patients like reducing myocardial damage, reversal of atrial fibrillation, and resolution of heart failure symptoms. Real-world outcomes and clinical trials show a consistent reduction in amyloid deposition, cardiovascular-related hospitalizations, and all-cause mortality with Tafamidis therapy. CONCLUSION: Tafamidis is an essential component of the treatment of ATTR-CM and this narrative review synthesizes the current evidence regarding safety, efficacy, and utilization in real practice. While it shows promising effects, its effectiveness may also vary and high cost precludes real-world large-scale studies. Overall, Tafamidis emerges as a valuable therapeutic option for managing ATTR-CM.

Transthyretin mutagenesis: impact on amyloidogenesis and disease.

Transthyretin (TTR), a homotetrameric protein found in plasma, cerebrospinal fluid, and the eye, plays a pivotal role in the onset of several amyloid diseases with high morbidity and mortality. Protein aggregation and fibril formation by wild-type TTR and its natural more amyloidogenic variants are hallmarks of ATTRwt and ATTRv amyloidosis, respectively. The formation of soluble amyloid aggregates and the accumulation of insoluble amyloid fibrils and deposits in multiple tissues can lead to organ dysfunction and cell death. The most frequent manifestations of ATTR are polyneuropathies and cardiomyopathies. However, clinical manifestations such as carpal tunnel syndrome, leptomeningeal, and ocular amyloidosis, among several others may also occur. This review provides an up-to-date listing of all single amino-acid mutations in TTR known to date. Of approximately 220 single-point mutations, 93% are considered pathogenic. Aspartic acid is the residue mutated with the highest frequency, whereas tryptophan is highly conserved. "Hot spot" mutation regions are mainly assigned to ß-strands B, C, and D. This manuscript also reviews the protein aggregation models that have been proposed for TTR amyloid fibril formation and the transient conformational states that convert native TTR into aggregation-prone molecular species. Finally, it compiles the various in vitro TTR aggregation protocols currently in use for research and drug development purposes. In short, this article reviews and discusses TTR mutagenesis and amyloidogenesis, and their implications in disease onset.

Amyloidosis and Amyloidogenesis: One Name, Many Diseases.

Amyloidosis is a heterogenous group of disorders, caused by the deposition of insoluble fibrils derived from misfolded proteins in the extracellular space of various organs. These proteins have an unstable structure that causes them to misfold, aggregate, and deposit as amyloid fibrils with the pathognomonic histologic property of green birefringence when viewed under cross-polarized light after staining with Congo red. Amyloid fibrils are insoluble and degradation-resistant; resistance to catabolism results in progressive tissue amyloid accumulation. The outcome of this process is organ disfunction independently from the type of deposited protein, however there can be organ that are specifically targeted from certain proteins.

Transthyretin amyloid cardiomyopathy in patients with unexplained increased left ventricular wall thickness.

Amyloid cardiomyopathy (CA) was previously considered a rare disease; however, rapid advancements in imaging modalities have led to an increased frequency of its diagnosis. The aim of this prospective study was to assess the prevalence and clinical phenotype of transthyretin amyloidosis (ATTR) cardiomyopathy in patients exhibiting unexplained increased left ventricular (LV) wall thickness. From 2020 to 2022, we enrolled 100 consecutive adults with unexplained increased LV wall thickness in the study. The analysis included clinical data, electrocardiography, transthoracic echocardiography, single-photon emission computed tomography/computed tomography with 3,3-disphono-1,2-propanodicarboxylic acid, genetic testing. Overall, 18% of patients were diagnosed with CA, comprising 5% with light-chain amyloidosis, and 12% with ATTR. To evaluate associations with the ATTR diagnosis, a LOGIT model and multivariate analysis were applied. Notably, age, polyneuropathy, gastropathy, carpal tunnel syndrome, lumbar spine stenosis, low voltage, ventricular arrhythmia, LV mass, LV ejection fraction, global longitudinal strain (GLS), E/A, E/E', right ventricle (RV) thickness, right atrium area, RV VTI, TAPSE, apical sparing, ground glass appearance of myocardium, thickening of interatrial septum, thickening of valves, and the "5-5-5" sign were found to be significantly associated with ATTR (p < 0.05). The best predictive model for ATTR diagnoses exhibited an area under the curve of 0.99, including LV mass, GLS and RV thickness. This study, conducted at a cardiology referral center, revealed that a very considerable proportion of patients with unexplained increased LV wall thickness may suffer from underlying CA. Moreover, the presence of ATTR should be considered in patients with increased LV mass accompanied by reduced GLS and RV thickening.

Parametric mapping using cardiovascular magnetic resonance for the differentiation of light chain amyloidosis and transthyretin-related amyloidosis.

AIMS: To evaluate different cardiovascular magnetic resonance (CMR) parameters for the differentiation of light chain amyloidosis (AL) and transthyretin-related amyloidosis (ATTR). METHODS AND RESULTS: In total, 75 patients, 53 with cardiac amyloidosis (20 patients with AL (66±12 years, 14 males [70%]) and 33 patients with ATTR (78±5 years, 28 males [88%])) were retrospectively analyzed regarding CMR parameters such as T1 and T2 mapping, extracellular volume (ECV), and late gadolinium enhancement (LGE) distribution patterns, and myocardial strain, and compared to a control cohort with other causes of left ventricular hypertrophy (LVH; 22 patients (53±16 years, 17 males [85%])). One way-ANOVA and receiver operating characteristic analysis were used for statistical analysis. ECV was the single best parameter to differentiate between cardiac amyloidosis and controls (area under the curve [AUC]: 0.97, 95% confidence intervals [CI]: 0.89-0.99, p<.0001, cutoff: >30%). T2 mapping was the best single parameter to differentiate between AL and ATTR amyloidosis (AL: 63±4 ms, ATTR: 58±2 ms, p<.001, AUC: 0.86, 95% CI: 0.74-0.94, cutoff: >61 ms). Subendocardial LGE was predominantly observed in AL patients (10/20 [50%] vs. 5/33 [15%]; p=.002). Transmural LGE was predominantly observed in ATTR patients (23/33 [70%] vs. 2/20 [10%]; p<.001). The diagnostic performance of T2 mapping to differentiate between AL and ATTR amyloidosis was further increased with the inclusion of LGE patterns (AUC: 0.96, 95% CI: 0.86-0.99]; p=.05). CONCLUSION: ECV differentiates cardiac amyloidosis from other causes of LVH. T2 mapping combined with LGE differentiates AL from ATTR amyloidosis with high accuracy on a patient level.

Six-minute walk test as clinical end point in cardiomyopathy clinical trials, including ATTR-CM: a systematic literature review.

Aim: The six-minute walk test (6MWT) is a common measure of functional capacity in patients with heart failure (HF). Primary clinical study end points in cardiomyopathy (CM) trials, including transthyretin-mediated amyloidosis with CM (ATTR-CM), are often limited to hospitalization and mortality. Objective: To investigate the relationship between the 6MWT and hospitalization or mortality in CM, including ATTR-CM. Method: A PRISMA-guided systematic literature review was conducted using search terms for CM, 6MWT, hospitalization and mortality. Results: Forty-one studies were identified that reported 6MWT data and hospitalization or mortality data for patients with CM. The data suggest that a greater 6MWT distance is associated with a reduced risk of hospitalization or mortality in CM. Conclusion: The 6MWT is an accepted alternative end point in CM trials, including ATTR-CM.

Kidney Amyloidosis: Updates on Pathogenesis and Therapeutic Frontiers.

BACKGROUND: Amyloidosis includes a diverse group of rare diseases characterized by the misfolding of native or mutant proteins, leading to extracellular accumulation in various organs. While 42 proteins have been identified to date, their distribution differs between systemic and localized forms. SUMMARY: Mass spectrometry analysis of tissue samples in the USA shows immunoglobulin light chain (AL) amyloidosis as the most prevalent systemic type, followed by transthyretin (ATTR). Heart and kidney involvements are common. Although there are 14 recognized types of kidney-related amyloidosis, clinicopathologic studies in the USA have identified 11 types, with AL amyloidosis being the most prevalent cause of kidney involvement. KEY MESSAGES: This review focuses on AL, AA, and ATTR amyloidosis due to their common systemic presentations. Recent US-based clinicopathologic studies challenge conventional beliefs that toxicity is primarily driven by amyloid deposition and highlight the role of the complement pathway. Diagnostic methods, particularly mass spectrometry, are crucial for accurate typing. Treatment strategies vary depending on the underlying type, with AL amyloidosis primarily targeting plasma cell clones, AA amyloidosis addressing underlying inflammation with systemic therapies, and ATTR amyloidosis focusing on ATTR stabilization or gene silencing.