Subtype Of Amyloidosis Research Articles

Adverse events following transcatheter aortic valve implantation (TAVI) in patients with amyloidosis: observations from a global federated network

Abstract Background A high proportion of patients with aortic stenosis are affected by cardiac amyloidosis, but there is a paucity of data describing the effect of amyloidosis on the clinical course of patients who underwent transcatheter aortic valve implantation (TAVI). Purpose To assess the one-year risk of adverse events following TAVI in patients with amyloidosis. Methods Retrospective study using data from a large multinational electronic health record network (TriNetX). Patients aged 18 years or older who underwent TAVI between 2005 and 2022 were included in the analysis. The patients were categorised in two groups based on the presence of amyloidosis (ICD-10-cm code E85). Primary outcome was the one-year risk of the composite of emergency department (ED) admission, acute heart failure (HF), stroke, conduction system disease, pacemaker (PM) implantation, acute kidney injury, and all-cause death. Secondary outcomes were the risks for each component of the composite outcome. We used Cox regression analysis to calculate hazard ratio (HR) and 95% confidence interval (CI) after propensity score matching (PSM) 1:1. Results We identified 477 TAVI recipients with a diagnosis of amyloidosis (age 78.6±8.1 years, 31.4% females) and 43,379 TAVI patients without a diagnosis of amyloidosis (78.1±8.8, 40.2% females). Before PSM, patients affected by amyloidosis were more likely to be Black or African American and had a higher prevalence of cardiovascular risk factors compared to TAVI patients without amyloidosis. After PSM, patients with a diagnosis of amyloidosis showed a higher one-year risk of composite outcome (HR 1.28, 95%CI 1.10-1.49) compared to those who underwent TAVI without amyloidosis. Regarding secondary outcomes, amyloidosis patients had a higher risk of ED admission (HR 1.41, 95%CI 1.13-1.75), acute HF (HR 1.56, 1.23-1.99), stroke (HR 1.55, 1.04-2.32), conduction system disease (HR 1.27, 1.04-1.55), PM implantation (HR 1.55, 1.06-2.28), but not acute kidney injury (HR 1.11, 0.84-1.48) and all-cause death (HR 0.98, 0.66-1.45). Conclusion Among patients undergoing TAVI, those affected by amyloidosis are at higher risk of adverse events in the first year after TAVI. More studies are needed to define the exact role of amyloid fibrils in structural valve deterioration and to elucidate whether subtypes of amyloidosis have a different impact on patients’ outcomes following TAVI.Risk of composite outcome following TAVI

Relative interventricular septal brightness for subtype diagnosis of cardiac amyloidosis: pixel brightness analysis using echocardiographic images

Abstract Background In the subtypes of cardiac amyloidosis (CA), transthyretin-related (ATTR) CA has been reported to exhibit a higher prevalence of microcalcifications in the interventricular septum (IVS) compared to other subtypes. Whether microcalcifications in the IVS can stratify CA subtypes remains unclear. Methods A total of 442 patients with CA: 76 light chain/ amyloid A (AL/AA) type; 255 wild type ATTR (ATTRwt) and 48 variant ATTR (ATTRv) and 19 patients with endomyocardial biopsy-confirmed hypertensive heart disease (HHD) were subjected to echocardiographic pixel brightness quantification of the IVS using open-access image analysis software. The IVS Brightness Index (IVSBI) was defined as the ratio of the average pixel brightness in the IVS to that in the left ventricular (LV) wall opposite the IVS (see figure 1). Results The IVSBI from apical 4-chamber view was higher in both the ATTRwt group (median 1.40, IQR 1.22 to 1.67) and the ATTRv group (1.59, 1.32 to 2.00) compared to the HHD group (1.20, 1.02 to 1.37) and the AL/AA group (1.25, 1.11 to 1.46), respectively (P <0.001, see figure 2). In the 273 CA patients undergoing myocardial technetium-99m-pyrophosphate scintigraphy, patients with positive results (1.41, 1.24 to 1.70) exhibited a higher IVSBI compared to those with negative (1.19, 1.09 to 1.46) (P = 0.006). In Cox proportional hazards analysis, age, gender and LV ejection fraction adjusted hazard ratio for the all-cause death of IVSBI (0.5 increase) was 2.0 (95% CI 1.2 to 3.5, P = 0.012) among ATTRwt patients (n=157). Conclusions An IVSBI obtained from the apical 4-chamber view could prove valuable in differentiating ATTR subtypes in CA, potentially revealing subtle septal calcifications. A prognostic value may be derived from the elevation of IVSBI in ATTRwt patients.figure 1figure 2

Differential echocardiographic profiles in immunoglobulin light chain and transthyretin amyloid cardiomyopathy: insights from speckle tracking analysis

Abstract Background Amyloid cardiomyopathy is mainly caused by two main subtypes of amyloidosis; immunoglobulin light chains cardiomyopathy (AL-CM) and transthyretin cardiomyopathy (TTR-CM). Purposes The aim of the present study was to elucidate the differences in echocardiographic findings between AL-CM and TTR-CM using speckle tracking echocardiography. Methods The study included patients with a confirmed diagnosis of cardiac amyloidosis through cardiac biopsy and who underwent transthoracic echocardiography between March 2013 and October 2022. The relative apical sparing index (RASI) was calculated using speckle tracking echocardiography: mean apical strain value/(mean basal strain value + mean mid strain value). Results The final study population consisted of 50 patients with a confirmed diagnosis of cardiac amyloidosis diagnosed pathologically (AL-CM: 21 patients, TTR-CM: 29 patients). Mean age was 72 ± 11 years, 70% being male. AL-CM exhibited a lower left ventricular mass index compared to TTR-CM (124.5 ± 48.9 vs. 152.2 ± 39.2 g/m2, P = 0.001). In 35 patients available with longitudinal strain analysis, no significant difference was observed in left ventricular global longitudinal strain between the two subgroups (-9.9 ± 4.8 vs. -9.3 ± 2.4% , P = 0.63). However, RASI was significantly lower in AL-CM compared to TTR-CM as shown in Figure (0.92 ± 0.29 vs. 1.46 ± 0.53, P = 0.001). Receiver operating characteristic curve analysis shows a RASI cut-off value of <1.0 proved useful in differentiating the diagnosis of AL-CM from TTR-CM (sensitivity: 81%, specificity: 70%, AUC:0.82), and RASI <1.0 remained a significant association with the diagnosis of AL-CM, even after adjusted by conventional echocardiographic variables. Conclusion Apical sparing phenomenon was more remarkable in TTR-CM compared with AL-CM, although global longitudinal strain was comparable between the two groups. RASI was useful for the discrimination of cardiac amyloidosis subtypes.

Automated Neural Architecture Search for Cardiac Amyloidosis Classification from [18F]-Florbetaben PET Images.

Medical image classification using convolutional neural networks (CNNs) is promising but often requires extensive manual tuning for optimal model definition. Neural architecture search (NAS) automates this process, reducing human intervention significantly. This study applies NAS to [18F]-Florbetaben PET cardiac images for classifying cardiac amyloidosis (CA) sub-types (amyloid light chain (AL) and transthyretin amyloid (ATTR)) and controls. Following data preprocessing and augmentation, an evolutionary cell-based NAS approach with a fixed network macro-structure is employed, automatically deriving cells' micro-structure. The algorithm is executed five times, evaluating 100 mutating architectures per run on an augmented dataset of 4048 images (originally 597), totaling 5000 architectures evaluated. The best network (NAS-Net) achieves 76.95% overall accuracy. K-fold analysis yields mean ± SD percentages of sensitivity, specificity, and accuracy on the test dataset: AL subjects (98.7 ± 2.9, 99.3 ± 1.1, 99.7 ± 0.7), ATTR-CA subjects (93.3 ± 7.8, 78.0 ± 2.9, 70.9 ± 3.7), and controls (35.8 ± 14.6, 77.1 ± 2.0, 96.7 ± 4.4). NAS-derived network performance rivals manually determined networks in the literature while using fewer parameters, validating its automatic approach's efficacy.

18F-Florbetaben PET/CT for the Diagnosis and Subtyping of Cardiac Amyloidosis: A Case Series and Review of the Literature.

Cardiac amyloidosis (CA) is a type of systemic amyloidosis. Amyloid-targeting positron emission tomography (PET) has shown potential as an imaging method for CA. However, the optimal imaging protocol and role of 18F-florbetaben (FBB) PET in the diagnosis and subtyping of CA have yet to be determined. Patients with suspected CA who had positive or equivocal results of technetium-99m pyrophosphate (PYP) scintigraphy were enrolled for dynamic and late FBB PET imaging. In addition to visual assessment, a kinetic modeling-based approach including target-to-background ratio (TBR) and myocardial retention fraction (RF) of serial images reconstructed from a 20-min dynamic acquisition, and a late image at 110 min post-injection were performed. We compared FBB PET measures of four typical patients with light chain amyloidosis (AL), wild-type transthyretin amyloidosis (ATTRwt), variant transthyretin amyloidosis (ATTRv), and heart failure, respectively. We also reviewed the literature on the clinical use of amyloid PET in CA. Myocardial tracer retention was only found in the AL patient on the late images. TBR and RF were highest in the AL patient followed by the ATTRwt patient, and lowest in the ATTRv and non-CA patients. FBB PET has potential in the detection and non-invasive subtyping of CA, especially in subjects with equivocal PYP findings or monoclonal gammopathy.

Pilot Study on the Use of Attenuated Total Reflectance-Fourier Transform Infrared Spectroscopy for Diagnosing and Characterizing Cardiac Amyloidosis.

Amyloidosis diagnosis relies on Congo red staining with immunohistochemistry and immunofluorescence for subtyping but lacks sensitivity and specificity. Laser-microdissection mass spectroscopy offers better accuracy but is complex and requires extensive sample preparation. Attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy offers a promising alternative for amyloidosis characterization. Cardiac tissue sections from nine patients with amyloidosis and 20 heart transplant recipients were analyzed using ATR-FTIR spectroscopy. Partial least squares discriminant analysis (PLS-DA), principal component analysis (PCA), and hierarchical cluster analysis (HCA) models were used to differentiate healthy post-transplant cardiac tissue from amyloidosis samples and identify amyloidosis subtypes [κ light chain (n = 1), λ light chain (n = 3), and transthyretin (n = 5)]. Leave-one-out cross-validation (LOOCV) was employed to assess the performance of the PLS-DA model. Significant spectral differences were found in the 1700-1500 cm-1 and 1300-1200 cm-1 regions, primarily related to proteins. The PLS-DA model explained 85.8% of the variance, showing clear clustering between groups. PCA in the 1712-1711 cm-1, 1666-1646 cm-1, and 1385-1383 cm-1 regions also identified two clear clusters. The PCA and the HCA model in the 1646-1642 cm-1 region distinguished κ light chain, λ light chain, and transthyretin cases. This pilot study suggests ATR-FTIR spectroscopy as a novel, non-destructive, rapid, and inexpensive tool for diagnosing and subtyping amyloidosis. This study was limited by a small dataset and variability in measurements across different instruments and laboratories. The PLS-DA model's performance may suffer from overfitting and class imbalance. Larger, more diverse datasets are needed for validation.

Clinical characterization of patients with cardiac amyloidosis in a referral center of Colombia.

The objective of the study is to describe the characteristics of our first cohort of amyloidosis in a Latin America cardiovascular reference center in Colombia. This is a historic cohort study and data were taken from the electronic records of the Fundación Cardioinfantil-Instituto de cardiología; adult patients with a diagnosis of cardiac amyloidosis were included and a descriptive analysis was presented. A total of 31 patients with amyloidosis were included. 17 were Transthyretin Amyloidosis (ATTR) subtype and 14 were AL subtype. An overall mortality of 25% was found. The mean age at diagnosis was 74 years, male sex predominant. More frequent comorbidities were hypertension and atrial fibrillation. The most frequent clinical presentation was congestive heart failure (75%), with mildly reduced ejection fraction (41.94%), followed by reduced ejection fraction (32.26%), and preserved ejection fraction (25.81%). In the ATTR subtype, a reduced ejection fraction was found at 41.18% and a mildly reduced ejection fraction at 35.29%. These results provide information on the most frequent type of amyloidosis and the late timing to diagnose in our historic cohort study, we present some of the baseline characteristics and most frequent approaches to diagnose Cardiac Amyloidosis that represents all challenges in clinical practice. Improvements are needed in the diagnosis and early treatment of these patients.

A bibliometric analysis of light chain amyloidosis from 2005 to 2024: research trends and hot spots.

Light chain (AL) amyloidosis stands as the most prevalent subtype of systemic amyloidosis, encompassing a group of rare diseases. Here, we evaluated the scientific landscape of AL amyloidosis to investigate research trends and identify hotspots within the field. Relevant studies on AL amyloidosis published over the past two decades were retrieved from the Web of Science Core Collection. The publications between 2005 and 2024 were subjected to bibliometric analyses, leveraging tools including CiteSpace, VOSviewer, RStudio and MS Excel to analyse and visualize the annual publication trend, co-occurrence patterns, collaborative networks among countries, organizations, and authors. Burst keywords and references were also examined to obtain the research history, and emerging hotspots. The bibliometric analysis included 2,864 articles published between 2005 and 2024. The most productive journal is Amyloid-Journal of Protein Folding Disorders. The United States, along with several developed nations, emerges as a dominant force in international AL amyloidosis research. "AL amyloidosis" and "cardiac amyloidosis" were the primary hotspots over the past two decades, and "Biomarkers," "Cardiac amyloidosis," and "treatment" would be future trends. This bibliometric analysis examined the research developments in AL amyloidosis over the past two decades using bibliometric software. Recent research in this field primarily focuses on two main areas: clinical diagnosis and treatment of AL amyloidosis, as well as cardiac amyloidosis. Emphasis is placed on understanding the mechanisms underlying immunoglobulin light chain aggregation and deposition to mitigate organ involvement.

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

Transthyretin cardiac amyloidosis (ATTR-CM) may be an underestimated cause of heart failure among geriatric patients and represent a unique phenotype and prognostic profile. 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 (<75years), and 612 (64.9%) were geriatric (≥75years). 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 (≥44ng/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. 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.

A novel mutation in the transthyretin gene in amyloidosis: A cluster case report in Vietnam

Transthyretin amyloidosis (ATTR) is a slowly progressive condition characterised by the abnormal accumulation of a protein called amyloid in the body’s organs and tissues. There are three main subtypes of amyloidosis (AL), including primary or AL, secondary or AA AL, and hereditary or familial AL. Hereditary AL, which is less common, is caused by an autosomal-dominant mutation, most frequently in the transthyretin (TTR) gene, and has a more favourable prognosis. We report the case of a 51-year-old Vietnamese male who presented with severe dizziness, fainting episodes, low BMI, slow heart rate, and a blood pressure of 60/40 mmHg. The patient had a history of diges-tive disorders, weakness, and pain in the legs even after disc spine surgery. All symptoms onset occurred at 43 years old. A pathogenic mutation in the TTR gene c.209G&gt;T was confirmed in the patient and 7 out of 15 individuals in his extended family. This is the first case reported in Vietnam diagnosing a new variant of TTR causing typical AL. Based on this study, we conclude that the TTR variant c.209G&gt;T is a pathogenic gene. This study also emphasises the need for increased knowledge regarding AL associated with this pathogenic variant. However, further extensive research is required to provide a comprehensive understanding of the pathogenesis of TTR in the future.

Historic characteristics and mortality of patients in the Swiss Amyloidosis Registry.

Systemic amyloidoses are rare protein-folding diseases with heterogeneous, often nonspecific clinical presentations. To better understand systemic amyloidoses and to apply state-of-the-art diagnostic pathways and treatment, the interdisciplinary Amyloidosis Network was founded in 2013 at University Hospital Zurich. In this respect, a registry was implemented to study the characteristics and life expectancy of patients with amyloidosis within the area covered by the network. Patient data were collected retrospectively for the period 2005-2014 and prospectively from 2015 onwards. Patients aged 18 years or older diagnosed with any subtype of systemic amyloidosis were eligible for inclusion if they were treated in one of the four referring centres (Zurich, Chur, St Gallen, Bellinzona). Baseline data were captured at the time of diagnosis. Follow-up data were assessed half-yearly for the first two years, then annually. Between January 2005 and March 2020, 247 patients were screened, and 155 patients with confirmed systemic amyloidosis were included in the present analysis. The most common amyloidosis type was light-chain (49.7%, n = 77), followed by transthyretin amyloidosis (40%, n = 62) and amyloid A amyloidosis (5.2%, n = 8). Most patients (61.9%, n = 96) presented with multiorgan involvement. Nevertheless, single organ involvement was seen in all types of amyloidosis, most commonly in amyloid A amyloidosis (75%, n = 6). The median observation time of the surviving patients was calculated by the reverse Kaplan-Meier method and was 3.29 years (95% confidence interval [CI] 2.33-4.87); it was 4.87 years (95% CI 3.14-7.22) in light-chain amyloidosis patients and 1.85 years (95% CI 1.48-3.66) in transthyretin amyloidosis patients, respectively. The 1-, 3- and 5-year survival rates were 87.0% (95% CI 79.4-95.3%), 68.5% (95% CI 57.4-81.7%) and 66.0% (95% CI 54.6-79.9%) respectively for light-chain amyloidosis patients and 91.2% (95% CI 83.2-99.8%), 77.0% (95% CI 63.4-93.7%) and 50.6% (95% CI 31.8-80.3%) respectively for transthyretin amyloidosis patients. There was no significant difference between the two groups (p = 0.81). During registry set-up, a more comprehensive work-up of our patients suffering mainly from light-chain amyloidosis and transthyretin amyloidosis was implemented.Survival rates were remarkably high and similar between light-chain amyloidosis and transthyretin amyloidosis, a finding which was noted in similar historic registries of international centres. However, further studies are needed to depict morbidity and mortality as the amyloidosis landscape is changing rapidly.

A Case of Amyloid Goitre in Heavy Chain Amyloidosis: Diagnostic Challenges and Clinical Implications.

Immunoglobulin heavy chain amyloidosis is an extremely rare subtype of immunoglobulin-derived amyloidosis and amyloid goitre is even rarer.There is limited literature on how to diagnose and manage this disorder.This case portrays one of these cases - one of the few existing in the literature - and reinforces the diagnostic complexity of this entity.

Weight loss, diarrhea, and polyneuropathy: could it be amyloidosis?

Background: Amyloidosis is a multisystemic disease that may be hereditary, characterized by the deposit of amyloid in the extracellular space. Transthyretin-mediated (ATTRm) amyloidosis is the most common subtype of heredofamilial amyloidosis. The diagnosis is based on clinical suspicion and amyloid in tissues. Hepatic transplantation is the only treatment that prevents the synthesis of the amyloidogenic variants of transthyretin protein. Case Presentation: A 34-year-old male presented with weight loss, gastrointestinal symptomatology, and polyneuropathy associated with histopathologic deposits of amyloid in gastrointestinal and fat tissue as well as peripheral nerve. Conclusion: Hereditary familial amyloidosis (HFA) is a relatively rare disorder that leads to erroneous and delayed definitive diagnosis. Therefore, the diagnosis should be first based on a suspicion of the disease, and then proceed according to complete protocol.

Real-World Outcomes and Treatment Patterns in AL-Amyloidosis in Austria: An Analysis from the Austrian Interdisciplinary Amyloidosis Registry (AIDA)

Introduction This project aimed to provide an overview of the treatment landscape for AL - Amyloidosis (AL-A) in Austria as documented in AIDA, the Austrian Interdisciplinary Amyloidosis Registry. By examining the existing body of knowledge surrounding treatments and demographics, we seeked to shed light on the potential benefits and challenges for new treatment modalities in the context of AL-A. Methods We identified 210 AL- pts. from AIDA (cut off May 15, 2023). Statistics were descriptive. Kaplan Meier was chosen for survival plots and analyses were carried out with Excel and SPSS. Results We present data from 210 AL-A pts. recruited from AIDA. This constitutes 45.95% of all pts. in AIDA, with the major parts of the residual population made up by wt-ATTR amyloidosis pts. (47.48%), with some rare other amyloidosis subtypes accounting for the rest. There was a male pre-dominance in the cohort (62.38%) well in line with published data. Pts. with AL-A were found to be much younger (median age 66a vs. 78a) compared to pts. suffering from wt-ATTR. Diagnosis of AL-A was made between 1997 and 2023, with the median year of first diagnosis being 2016, resulting in median follow up in the cohort of ~ 7 years. The pattern of organ involvement by AL-A were quite typical with heart (78.6%), kidney (58.1%), GI-tract (23.3%) and PNS (21.4%) being the dominant manifestations. Advanced stages by either the classical Mayo staging, as well as the revised one were regrettably still by far more frequent at time of diagnosis as early disease stages (classical Mayo III in 65.8%, and revised MAYO III and IV in 27.8% and 42.3% of pts. respectively). This is mirrored in a high number of pts. with severe to moderate renal insufficiency (GFR &amp;lt; 30ml/min in 4.6% and between 30-60 ml/min in 42.2% of pts.) and/or moderate to severe cardiac involvement (NT-pro BNP &amp;gt; 5000 ng/l in 37.2%, and between 500 - 5000 ng/l in another 51.2% of pts.). Detailed data on comorbidities and toxicities will be added. Treatments Only 141/210 pts. ever received a documented 1 st line of treatment (LoT), of which only 35.5% received a 2 nd LoT, and even less a 3 rd LoT (20.6%), while more LoTs were applied only in a handful of pts. This horrendous attrition rate per LoT is far above, what has been described for Myeloma (20% / LoT). Time to next tretament was found to be median of 9.9 months. 54 pts. received a 1st LoT with the intent of pursuing an autologous stem cell transplantation (ASCT), but only 54% of these actually were transplanted. This compares inferior to Myeloma, although MM pts. are usually significantly older. The most frequently used therapeutic regimes were VCd-D (Andromeda) with or without Dara-maintenance. The widespread use of anti-CD38 based treatments in this sub-cohort is mirrored in a quite high rate of high-quality hematologic responses (CR+VGPR = 51.9%). 90 pts. received 1st LoTs not intending to lead to ASCT. Again, Daratumumab based regimes were the most used, but treatment outcomes were much inferior (hematologic CR+ VGPR = 18.9%) probably based on dosages, time on therapy, and not applied ASCT. Only 40 pts. received conventional 2nd LoTs usually classical Myeloma therapies, with modest treatment results. Even hematologic high-quality responses (CR+VGPR = 25%) were rare not to mention organ responses. Survival Median survival in the AIDA cohort was found to be 45 months. Broken down by Mayo stages, both classic and revised, was found to be quite unfavorable for advanced disease (14 months in revised Mayo stage IV or classical Mayo stage III). Conclusions Compared to other plasma cell dyscrasias overall outcomes in AL-A are still dismal, despite the introduction of recent effective anti-plasma cell therapeutics in the treatment algorithm. Disease modifying therapies are urgently needed and should be preferentially introduced in 1 st line, as only few pts. will receive 2 nd or later LoTs. Furthermore, efforts to improve awareness for this dreadful disease are urgently needed to enable more therapies to be applied in less advanced disease settings. Take home-messages: 1. Efforts needed to improve early diagnosis of AL-A when treatment options will not be hampered by progressive organ dysfunctions 2. Absolute necessity to explore disease modifying therapies going beyond stopping excess free light chain production 3. As only a limited number of pts. received multiple LoTs any new therapeutics should be integrated in effective 1 st LoTs preferentially.

Abstract 16233: Paradoxical Coronary Embolus Associated With Right Atrial Thrombus in Cardiac Amyloidosis

Introduction: This case highlights amyloidosis’ risk for intracardiac thrombosis with an atypical presentation of paradoxical coronary embolism due to right atrial thrombus. Clinical Presentation: An 87-year-old male with atrial fibrillation not on anticoagulation, HFrEF, severe mitral regurgitation, CKD3B, and recent medically managed NSTEMI, presented with shortness of breath. Labs showed elevated Troponin-T HS (174 ng/L) and proBNP (11,955 pg/mL). Echocardiogram revealed EF 25-30% with new lateral and anterior wall akinesis, concerning for NSTEMI I. Coronary catheterization revealed possible thrombus in the left circumflex artery (Figure 1A), but distal perfusion was intact. CT angiogram was negative for coronary artery dissection, providing clearance to initiate treatment with Eliquis. Intriguingly, cardiac MRI suggested intracardiac thrombus within the right atrial appendage and patent foramen ovale (Figure 1B), and possible amyloidosis from delayed gadolinium uptake. Despite negative serologic amyloid workup, pyrophosphate scan confirmed transthyretin amyloidosis. The patient was diuresed for decompensated heart failure but hypotension and acute-on-chronic kidney disease limited Guidelines-Directed Medical Therapy at discharge. Discussion: This case elucidates the importance of recognizing the thromboembolic risk in cardiac amyloidosis patients. Studies indicate up to 30% of cardiac amyloidosis patients have intracardiac thrombi, particularly those with primary amyloidosis subtype. Notably, no correlation exists between the CHA2DS2-VASc score and the presence of left atrial appendage thrombus in patients with cardiac amyloidosis and atrial fibrillation. Despite the left atrial appendage being twice more susceptible to thrombus formation, the right atrial appendage requires attention. Timely screening in high-risk patients could enable early thrombus detection, potentially improving prognosis.

Evolución de los subtipos, características clínicas y métodos diagnósticos de la amiloidosis en un registro institucional

Introduction and objectivesAmyloidosis is a rare disease. Advances in understanding and diagnosis have increased detection of the disease. Our objective was to describe the evolution in the distribution of amyloidosis subtypes, the clinical characteristics and diagnostic methods used in an Institutional Registry of Amyloidosis in Argentina over 18 years. MethodsConsecutive patients with AL amyloidosis, ATTR wild type, ATTR variant, and AA between 1 January 2005 and 31 December 2022 were included. The evolution in the distribution of subtypes, clinical characteristics and diagnostic modalities was analyzed in three subperiods: 2005-2010; 2011-2016; 2017-2022. ResultsA total of 258 patients were included. The distribution of amyloidosis subtypes varied throughout the study period. AL amyloidosis was the most frequent in the first subperiods (85% and 63% respectively), while ATTR wild type amyloidosis predominated in the last subperiod (49%) (P<.001). The age at diagnosis increased from 60 years [interquartile range (IIC): 52-69] between 2005-2010 to 76 years [IIC: 66-83] between 2017-2022 (P<.001). Heart failure was common in all subperiods, with an increase in the last one. The history of carpal tunnel was observed more in the last subperiod. ConclusionsIn this study we observed an increase in the detection of cases of systemic amyloidosis and ATTR wild type in particular. In addition, a transition towards non-invasive diagnostic methods was evidenced, such as DPD scintigraphy, reflecting technological advances in disease detection.

Bayesian Convolutional Neural Networks in Medical Imaging Classification: A Promising Solution for Deep Learning Limits in Data Scarcity Scenarios

Deep neural networks (DNNs) have already impacted the field of medicine in data analysis, classification, and image processing. Unfortunately, their performance is drastically reduced when datasets are scarce in nature (e.g., rare diseases or early-research data). In such scenarios, DNNs display poor capacity for generalization and often lead to highly biased estimates and silent failures. Moreover, deterministic systems cannot provide epistemic uncertainty, a key component to asserting the model’s reliability. In this work, we developed a probabilistic system for classification as a framework for addressing the aforementioned criticalities. Specifically, we implemented a Bayesian convolutional neural network (BCNN) for the classification of cardiac amyloidosis (CA) subtypes. We prepared four different CNNs: base-deterministic, dropout-deterministic, dropout-Bayesian, and Bayesian. We then trained them on a dataset of 1107 PET images from 47 CA and control patients (data scarcity scenario). The Bayesian model achieved performances (78.28 (1.99) % test accuracy) comparable to the base-deterministic, dropout-deterministic, and dropout-Bayesian ones, while showing strongly increased “Out of Distribution” input detection (validation-test accuracy mismatch reduction). Additionally, both the dropout-Bayesian and the Bayesian models enriched the classification through confidence estimates, while reducing the criticalities of the dropout-deterministic and base-deterministic approaches. This in turn increased the model’s reliability, also providing much needed insights into the network’s estimates. The obtained results suggest that a Bayesian CNN can be a promising solution for addressing the challenges posed by data scarcity in medical imaging classification tasks.

Prevalence, Predictors and Diagnosis of Cardiac Amyloidosis in Patients with Aortic Stenosis

Cardiac amyloidosis and aortic stenosis often share a common clinical phenotype, and are associated with morbidity and mortality if untreated. Cardiac amyloidosis is present in ~15% of patients with aortic stenosis. Clinical suspicion for cardiac amyloidosis in aortic stenosis is often raised based on history (bilateral carpal tunnel syndrome, severe lumbar spinal stenosis, spontaneous biceps rupture), chronic troponin elevation, electrocardiographic features (low-voltage criteria, pseudoinfarct pattern), echocardiogram (bilateral ventricular hypertrophy, abnormal longitudinal strain) and magnetic resonance imaging (late gadolinium enhancement, elevated T1 and T2). Eventual diagnosis of cardiac amyloidosis is based either on pyrophosphate nuclear scintigraphy or tissue biopsy depending on which subtype of cardiac amyloidosis is suspected.

Status and Future Directions of Therapeutics and Prognosis of Cardiac Amyloidosis.

Accumulation of aberrant proteins in the heart causes cardiac amyloidosis, an uncommon and complicated illness. It can be classified into two main types: light chain (AL) and transthyretin (ATTR). The diagnosis of cardiac amyloidosis is challenging due to its non-specific clinical presentation and lack of definitive diagnostic tests. Diagnostic accuracy has increased with the advent of modern imaging methods, including cardiac magnetic resonance imaging (MRI) and positron emission tomography (PET) scans. Depending on the severity of cardiac amyloidosis, a number of treatments may be attempted and specified according to the subtype of amyloidosis and the presence of complications. However, there are still significant challenges in treating this condition due to its complexity and lack of effective treatments. The prognosis for patients with cardiac amyloidosis is poor. Despite recent advances in diagnosis and treatment, there is still a need for more effective treatments to improve outcomes for patients with this condition. Therefore, we aim to review the current and future therapeutics reported in the literature and among ongoing clinical trials recruiting patients with CA.

#4952 CLINICOPATHOLOGIC CORRELATIONS OF URINARY PROTEOMIC AND METABOLOMIC ANALYSIS IN PATIENTS WITH RENAL AA AMYLOIDOSIS AND MEMBRANOUS NEPHROPATHY

Abstract Background and Aims AA Amyloidosis is a multisystemic amyloidosis subtype that develops on the background of various chronic inflammatory etiologies. Urinary omics studies have become a promising tool for elucidating pathophysiology and prognosis of glomerular diseases. However, no urinary omics analysis has been performed focusing on renal AA amyloidosis in literature to the best of our knowledge. Our main aim in this study is to perform a comparative urine proteomic and metabolomic analysis of recently diagnosed renal AA amyloidosis and to investigate the correlation of bioinformatic results with clinical and pathological data. Method Urine samples of 8 recently diagnosed AA amyloidosis (AA), 8 membranous nephropathy (MN) and 6 healthy control group patients were collected before kidney biopsy procedure. Proteomic analyzes were performed with nLC/Q-TOF MS/MS and metabolomic analyzes were performed by GC/MS in all patients. Biopsy specimens were scored according to glomerulosclerosis (G), tubular atrophy (TA) and interstitial fibrosis (IF) grades by two pathologists. Raw spectroscopic data was analyzed using MaxQuant and MS-DIAL programs for proteomic and metabolomic studies, respectively. Statistical analysis of the differences in molecules between study groups were performed with ANOVA and HSD-Tukey tests. Principal component (PCA) and heatmap analyzes were made in R language, while gene ontology (GO), network and functional enrichment analysis of bioinformatic results were performed with PANTHER, STRING and MetaboAnalyst databases. Results In comparison between AA and MN groups, median eGFR values tend to be lower in the AA group (67.6 vs 112 ml/min/1.73 m2 respectively, p = 0.08). Median 24-hour urine protein levels did not show statistically significant difference (9499 vs 9512 mg/day respectively, p = 0.9). Percentage of patients with moderate/severe IF/TA was higher and G score was tend to be in AA group compared to MN group (p values 0.02 and 0.07 for IF/TA and G scores, respectively). As a result of proteomic analysis, a total of 859 proteins were determined. Statistical analysis showed 51 proteins that were significantly differ in AA group compared to the control group. GO and functional enrichment analyzes showed that statistically most significant sub-domains were mainly related with cell-cell adhesion (Figure 1 &amp; 2). In comparative analysis between AA and MN patients, uromodulin (UMOD) was lower in the AA group than in the MN group (log2FC -3.37), whereas ribonuclease 1 (RNASE1) and α-1-microglobulin/bikunin precursor protein (AMBP) were higher in the AA group (log2FC 3.41 and 3.07, respectively). In Spearman correlation analyzes, significant negative correlations were demonstrated between UMOD-proteinuria (r = -0.48, p = 0.03) and between AMBP-eGFR (r = -0.69, p = 0.003) variables. Metabolomic analysis showed 9 metabolites that were significantly different between AA and other study groups. Myo-inositol and urate were higher in AA group compared to MN group, while D-mannitol and N-acetylglutamate were higher in AA group compared to the control group. Significant positive correlation independent of GFR was detected between RNASE1 and urate (r = 0.63, p = 0.01). Conclusion Our study is the first urinary comparative omics analysis performed on renal AA amyloidosis patients to the best of our knowledge. We demonstrated specific protein and metabolites that distinguish AA group from the control and MN groups. Enrichment and GO analyzes between AA and the control group showed a negative enrichment in cell-cell adhesion related sub-domains, suggesting a possible increased urinary shear stress resulting in downregulation of cadherins in AA amyloidosis. In comparative analysis between AA and MN groups, UMOD and AMBP proteins and myo-inositol were thought to be associated with high tubulointerstitial damage, whereas RNASE1 and urate were believed to be related with systemic inflammation and endothelial damage [1].