Amyloidosis Research Articles

Abstract 4144567: Prevalence of Atrial Fibrillation in Amyloidosis and Their Association: A 5-Year Nationwide Analytical Cross-Sectional Study

Background: Atrial fibrillation (AF) is a common cardiac arrhythmia associated with significant morbidity and mortality. Amyloidosis (AM) is characterized by the accumulation of amyloid protein in various anatomical sites, including the heart, atria, and ventricles. This amyloid infiltration leads to adverse chamber remodeling, predisposing patients to tachyarrhythmias such as atrial fibrillation/flutter. This study aims to re-evaluate the association of AM with AF by using the large nationwide inpatient database over a total duration of 5 years. Methods: An analytical cross-sectional study was conducted utilizing the data from a survey-weighted national inpatient sample database covering admissions from Jan 2017 to Dec 2021. A total of 147,015,073 admissions of patients aged 18 years and above were included. Descriptive statistics and univariate logistic regression models were used to calculate prevalence rates and odds ratios (OR), respectively. The multivariate logistic regression model was then used to adjust various potential confounders, including age, gender, race, income, hypertension, diabetes, stage 3 or above chronic kidney disease (CKD), Charlson comorbidity index, and hospital-related factors. Results: The 5-year prevalence of AF was 36.73% and 15.42% in admissions with and without AM, respectively. Significant differences between the with AM and without AM groups were in mean ages (72.40 vs. 58.08), female (41.83% vs. 56.92%), race of Black (24.57% vs. 15.40%), and CKD stage 3+ (44.83% vs. 16.65%), respectively. The univariate logistic regression analysis showed an OR for AF of 3.18 (95%CI: 3.102 - 3.267, P<0.000) in admissions with AM compared to those without. After adjustment for the potential confounders, the OR for AF decreased to 1.64 (95%CI 1.597- 1.686; P<0.000) in patients with Amyloidosis compared to those without. Conclusion: This study confirms a significant association between amyloidosis and atrial fibrillation, demonstrating that patients with amyloidosis have a markedly higher prevalence of atrial fibrillation compared to those without. Univariate analysis showed an odds ratio of 3.18 for atrial fibrillation in amyloidosis patients, which remained significantly elevated at 1.64 after adjusting for confounders. These findings indicate the need for a comprehensive workup of suspected atrial fibrillation in amyloidosis patients. Further research should investigate the mechanisms behind this association and potential prevention.

Abstract 4138014: Incidence and Association of Amyloidosis Found at Carpal Tunnel Release to Development of Cardiac Involvement

Background: Carpal tunnel syndrome (CTS) associated with transthyretin cardiac amyloidosis (ATTR-CA) may manifest 5 to 10 years prior to cardiac diagnosis. Transthyretin amyloidosis (ATTR) identification in the tenosynovium isolated during carpal tunnel release (CTR) may facilitate earlier ATTR-CA diagnosis and treatment. Hypothesis: Amyloid discovered at CTR will be associated with, and/or serve as a precursor for, cardiac involvement. Aim: We aimed to determine the frequency and type of amyloid found at CTR as well as the incidence of cardiac involvement and/or treatment indication. Methods: A retrospective analysis was conducted on a convenience sample of adults undergoing CTR from 01/05/2021 to 03/24/2023. Biopsy specimens with confirmed amyloid via Congo red staining were analyzed using mass spectrometry (MS) for subtyping. Patients with amyloid in tenosynovial tissue were offered cardiac evaluation with history and physical, electrocardiogram, B-type natriuretic peptide, troponin-I HS, echocardiogram, and TcPYP nuclear scintigraphy. Patients with light-chain amyloidosis (AL) were referred to oncology, while patients with ATTR were offered genetic testing. Results: A total of 578 patients underwent CTR with tenosynovial sample excision. Amyloid involvement by Congo red staining was found in 43 patients (7.4%), with a definitive subtype confirmed by MS in 30 patients (5.2%). Samples were insufficient to define subtypes in 13 patients. Sole ATTR was found in 27 patients (4.7%), both AL and ATTR were found in 1 patient, and sole AL was found in 2 patients. Of the 28 ATTR patients (the patient with both ATTR and AL included), 24 pursued genetic testing, revealing all had wild-type ATTR. Of these 28 patients, 21 underwent cardiac evaluation, for which 2 had cardiac involvement on TcPYP and started tafamidis therapy. The patients with concomitant ATTR and AL or sole AL did not have evidence of cardiac involvement, however, chemotherapy was initiated as indicated. Unfortunately, 1 patient with AL on CTR did not pursue an evaluation. Conclusion: Incidental amyloid tissue found at CTR is common and associated with occult involvement warranting therapy in a minority of cases. Future cardiac involvement is unknown, and this cohort will be followed to determine future incidence. A startling number of patients were found to have occult systemic AL discovered at CTR. These incidental diagnoses may trigger lifesaving interventions, which may otherwise go undiagnosed.

Abstract 4131488: Artificial Intelligence-Enhanced Electrocardiogram for the Diagnosis of Cardiac Amyloidosis: A Systemic Review and Meta-analysis

Background: Diagnosis of cardiac amyloidosis (CA) is often delayed due to variability in clinical presentation. The electrocardiogram (ECG) is one of the most common and widely available tools for assessing cardiovascular diseases. Artificial intelligence (AI) models analyzing ECG have recently been developed to detect CA, but their pooled accuracy is yet to be evaluated. Aim: To meta-analyze the accuracy of AI-enhanced ECG in diagnosing CA. Methods: We searched the Scopus, MEDLINE, and Cochrane CENTRAL databases up until April 2024 for studies assessing AI-enhanced ECG diagnosis of CA. Studies reporting findings from derivation and validation cohorts were included. Studies combining other diagnostic modalities such as echocardiography were excluded. The outcome of interest was the area under the receiver operating characteristic curve (AUC) for overall CA and subtypes transthyretin amyloidosis (ATTR) and light chain amyloidosis (AL). Analysis was done using RevMan 5.4.1 general inverse variance random effects model, pooling data for AUC and 95% confidence intervals (CI). Results: 5 studies comprising 7 cohorts met the eligibility criteria. The total derivation and validation cohorts were 8,639 and 3,843 respectively. The AUC were 0.89 (95% CI, 0.86-0.91) for cardiac amyloidosis, 0.90 (95% CI, 0.86-0.95) for ATTR amyloidosis and 0.80 (95% CI, 0.80-0.93) for AL amyloidosis. The forest plots can be found in the Figure 1. Conclusion: AI-enhanced ECG models effectively detect CA and may provide a useful tool for the early detection and intervention of this disease.

A descriptive analysis of 21 patients with pulmonary amyloidosis: An observational study

Pulmonary amyloidosis is an extremely rare disease, often detected incidentally because of its asymptomatic nature and potential to result in fatal outcomes. In this study, we aimed to present the clinical and radiological features of patients diagnosed with pulmonary amyloidosis by biopsy. This descriptive study included 21 patients with pathologically diagnosed pulmonary amyloidosis. Pulmonary amyloidosis was classified as diffuse alveolar-septal amyloidosis (DASA), cystic amyloidosis (CPA), tracheobronchial amyloidosis (TBA), nodular amyloidosis (NPA), and extraparenchymal pulmonary amyloidosis (pleural and mediastinal lymph node). Clinical, bronchoscopic, and radiological specific characteristics were presented in detail to be used for differential diagnosis. The median age of the patients was 63 (40–83) years, and 14 (66.7%) were male. Twenty patients (95.2%) presented with at least 1 comorbidity. All patients diagnosed with tracheobronchial amyloidosis were symptomatic at presentation, whereas those diagnosed with NPA/extraparenchymal amyloidosis were often asymptomatic. The patients included 1 case of DASA, 1 case of CPA, 10 cases of NPA, 6 cases of TBA, and 3 cases of extraparenchymal amyloidosis involving the mediastinal lymph node and pleura. Sixteen patients (76.2%) were classified as localized amyloidosis, while 5 patients (23.8%) were classified as systemic amyloidosis following the diagnosis of multiple myeloma, monoclonal gammopathy of undetermined significance, systemic lupus erythematosus, Sjogren’s syndrome, and B-cell lymphoma. Bronchoscopic biopsies were sufficient for diagnosis, and notably, even transbronchial needle aspiration could be a useful diagnostic method. During the follow-up, we observed that the disease remained stable without progression. However, it is important to note that patients with concurrent malignancies experience fatal outcomes. In conclusion, it is crucial to distinguish pulmonary amyloidosis from other pulmonary diseases such as malignancies, infectious diseases, and interstitial lung diseases, which may have similar clinical and radiological findings. Bronchoscopic diagnostic methods are usually sufficient for the diagnosis. Although patients with pulmonary involvement mostly remain stable during long-term follow-up without progression, it is important to consider the risk of malignancy.

Higher detectability of amyloid with phenol Congo red compared with alkaline Congo red

IntroductionAmyloidosis is a heterogeneous group of conditions associated with tissue deposition of insoluble abnormal proteins that damage vital organs. Early diagnosis, when the deposits are minimal, determines the prognosis and requires histological confirmation. The commonly adopted gold standard technique is alkaline Congo red (ACR) staining, though its sensitivity is limited. There is a need for a simple and inexpensive screening method offering a better chance of detecting mini­mal amyloid deposits. The aim of this study was to compare amyloid detectability with ACR and phenol Congo red (PHCR) staining techniques for early detection of minimal deposits.Material and methodsWe assessed 452 tissue specimens (including adipose tissue, gastrointestinal mucosa, labial salivary gland, myocardium, and bone marrow) from 425 patients with clinically suspected systemic or local amyloidosis, which had been sent to the Pathology Laboratory of the National Institute of Geriatrics, Rheumatology and Rehabilitation in Warsaw. Adjacent sections from each specimen were stained with ACR and PHCR. If amyloid was detected, immunohistochemical typing was conducted. The consistency of the two staining methods was expressed as Cohen’s κ coefficient.ResultsA total of 169 tissue specimens (37%) yielded positive readings, with 93 cases ACR(+) and PHCR(+); 75 cases ACR(–) and PHCR(+), and 1 case ACR(+) and PHCR(–). The percentage agreement between the staining methods was 83%, with the Cohen’s κ coefficient value of 0.60 (95% CI: 0.52–0.69), which corresponds to moderate agreement according to Fleiss. Additional immunohistochemical amyloid typing, conducted in ACR(–) and PHCR(+) specimens, yielded conclusive results in 82% of cases.ConclusionsThe use of PHCR staining as a screening method in suspected amyloidosis improves amyloid (light chain, transthyretin, and amyloid A protein) detectability in various tissues. The PHCR staining specificity should be verified via electron microscopy and/or mass spectrometry.

Single-center analysis of cardiac amyloidosis using 99mTc-HMDP imaging for diagnosis and evaluation after tafamidis treatment.

This study aimed to evaluate the diagnostic performance of 99mTc-hydroxymethylene diphosphonate (99mTc-HMDP) imaging for cardiac amyloidosis and to demonstrate changes in cardiac uptake of 99mTc-HMDP after tafamidis treatment. Seventy-five patients with suspected cardiac amyloidosis who underwent 99mTc-HMDP imaging were included. We compared visual Perugini grades and semiquantitative heart-to-contralateral (H/CL) area ratios, myocardial maximum standardized uptake value (SUVmax), and peak of SUV (SUVpeak) between cardiac transthyretin amyloidosis (ATTR) and amyloid light-chain amyloidosis (AL). Comparison of interobserver reproducibility between H/CL ratios and myocardial SUVmax/SUVpeak was performed. H/CL ratio of 99mTc-HMDP and myocardial SUVmax/SUVpeak were compared before and after tafamidis administration for cardiac wild-type ATTR. Among 75 patients, 20 patients (26.7%) were visually positive based on Perugini grade. Fifteen and three patients were pathologically identified as cardiac ATTR and AL, respectively. ATTR group (n = 15) had significantly higher H/CL ratios of 99mTc-HMDP than AL group (n = 3) (P = 0.003). ATTR group (n = 15) had significantly higher myocardial SUVmax/SUVpeak of 99mTc-HMDP than AL group (n = 2) (P = 0.015). Myocardial SUVmax/SUVpeak had better interobserver reproducibility than H/CL ratios. After tafamidis treatment for cardiac wild-type ATTR, the decrease in myocardial SUVpeak was significant but not in H/CL ratios and myocardial SUVmax. H/CL ratio and SUVmax/SUVpeak in 99mTc-HMDP imaging were useful for diagnosing cardiac ATTR. Myocardial SUVpeak may be useful for monitoring changes in cardiac uptake after tafamidis treatment for cardiac ATTR.

Warning values of serum total kappa/lambda ratio for M-proteinemia

BackgroundTo introduce the serum total kappa/lambda ratio (K/L) in humoral immunity testing reports to improve the detection rate of M-proteinemia.Methods156 M protein-positive and 5464 M protein-negative samples confirmed by serum immunofixation electrophoresis(sIFE) were accumulated from January 2021 to December 2023 in the First Affiliated Hospital of Soochow University and the contents of immunoglobulins (IgG, IgA, IgM, kappa and lambda) were tested by Beckman IMMAGE800. All the samples were divided into two groups by time: the modeling group and the validation group. The K/L values in the modeling group were analyzed by SPSS 27.0 to get the receiver operating characteristic curve (ROC). Furthermore, a more in-depth analysis was conducted to verify the reliability of the optimal cutoff values in the validation group. In addition, the levels of immunoglobulins of another group including 106 patients with definite diagnosis of monoclonal gammopathy ranging from January 2021 to June 2024 were traced back to improve the diagnostic efficiency.ResultsThe optimal cutoff values of K/L were 2.31 and 1.43 corresponding to K-type and L-type M-proteinemia respectively by ROC analysis. The sensitivity and specificity were validated as 76.14% and 77.42%. False positives were mainly found in samples with systemic sclerosis (36.84%), hypohepatia (28.71%) and sicca syndrome (27.27%). While false negatives were mainly found in IgA monoclonal gammopathy (38.39%) and IgM monoclonal gammopathy (28.57%). Combining with the detection rules of IgG, IgA and IgM, the sensitivities for the diagnosis of immunoglobulin light chain amyloidosis(AL) and monoclonal gammopathy of undetermined significance(MGUS) can be increased to 83.33% and 85%.ConclusionsK/L > 2.31 and K/L < 1.43 can be used as warning values for M-proteinemia. In addition, the content of the heavy chain in IgA- or IgM-type M-proteinemia may be considered to improve the detection rate.

Usefulness of scintigraphy with [99mTc]Tc-DPD for the detection of transthyretin cardiac amyloidosis. Reference centre experience in an endemic area

Abstract Background Cardiac amyloidosis (CA) is an infiltrative disorder caused by protein deposition, being transthyretin amyloidosis (ATTR) and primary amyloidosis (AL) the most common forms of CA. ATTR can occur in a hereditary form (ATTRv) or wild-type (ATTRwt). Our area is endemic for ATTRv due to the Val30Met mutation. Purpose To analyse the usefulness of scintigraphy with [99mTc]Tc-DPD (DPD-CS) in an endemic area and its relationship with the diagnostic of CA. Methods We conduct a retrospective study (04/2013-12/2022) of DPD-CS performed for suspected/screening of CA. Our acquisition protocol consists of performing planar images after 3h p.i.(anterior, left anterior oblique and left lateral) +/- SPECT/CT. The assessment of myocardial uptake was evaluated using the Perugini scale (PS: 0-3), considering 2 and 3 as positive scans. DPD-CS results were classified based on the suspicion of CA, according to the 2021 ESC guidelines (we considered cardiomyopathy if: left ventricle hypertrophy ≥12 mm + ≥3 typical signs/symptoms), as well as according to their final diagnosis: ATTRv, asymptomatic carriers, ATTRwt, AL, AA and other non-amyloid (NA) causes. Clinical findings were correlated with the results of the DPD-CS. Results 509 DPD-CS were performed in 478 patients (median age:73 years [22-95], 62% men). Median follow-up: 4.17 years. 127/478 patients were classified with cardiomyopathy (131/509 DPD-CS) and 351/478 without cardiomyopathy (378/509 DPD-CS). 115/509 positive DPD-CS (PS-2: 17, PS-3: 98): 113 had cardiomyopathy (55 ATTRv, 60 ATTRwt) and 2 without cardiomyopathy (1 ATTRv, 1 asymptomatic carrier). These latter two patients developed cardiomyopathy during the follow-up. 394/509 negative DPD-CS (PS 0: 387, PS 1: 7): 18 with cardiomyopathy (1 ATTRv, 1 carrier, 3 AL and 13 NA) and 376 without cardiomyopathy (30 asymptomatic carriers, 88 ATTRv, 2 AA, 9 AL and 247 NA). One patient with cardiomyopathy and ATTRv had initial negative DPD-CS, but became positive DPD-CS on follow-up. All ATTRv without cardiomyopathy presented polyneuropathy. Final diagnoses (according to DPD-CS number): 143 ATTRv (140 Val30Met, 2 Val122Ile, 1 Glu495Gln), 32 carriers (29 Val30Met, 2 Val122Ile, 1 His51Asn), 61 ATTRwt,12 AL, 2 AA and 259 NA. The analysis obtained after correlating the results of the DPD-CS regarding the presence of cardiomyopathy was: sensitivity 86.25%, specificity 99.47%, PPV 98.26% and NPV 95.43%. Conclusion Our study reaffirms the usefulness of DPD-CS in the non-invasive diagnosis of transthyretin CA. DPD-CS has an additional value in endemic areas for the early detection of CA in asymptomatic patients.

Heart Failure with Preserved Ejection Fraction and Cardiac Amyloidosis in the Aging Heart

Heart Failure with Preserved Ejection Fraction (HFpEF) is one of the most frequent causes of heart failure in the world’s population (about 19–55%), and is commonly associated with a high rate of hospitalization (almost 70–80%) and with increased mortality (40–50% in a 5-year timeframe). The elderly are more often affected, with higher rates of hospitalizations than young people, and currently almost 70% of the population aged 65 years old has HFpEF. An increase in cardiomyocyte stiffness, thus resulting in diastolic dysfunction, increased filling pressures and heart failure with preserved ejection fraction are characteristics features of the disease. In addition, among the various causes of HFpEF, cardiac amyloidosis (CA) can provoke diastolic dysfunction and increased wall stiffness directly from intercellular deposition of insoluble proteic substances and their toxic activity. Totally, almost 30 different proteins are able to form deposits, but the most frequently involved are transthyretin and misfolded monoclonal immunoglobulin light chains, which bring to two clinical conditions called transthyretin amyloidosis (ATTR) and light-chain amyloidosis (AL). Although there has been increasing attention on ATTR-CA in recent years, the actual prevalence remains underestimated, especially in people of advanced age, as well as its real impact as a cause of HFpEF, and only data derived from autoptic exams are currently available. Moreover, CA itself often mimics HFpEF, and some conflicting data on the use of predictive scores are described in the literature. The close relationship between HFpEF and CA, especially in older population and the main pathophysiological mechanisms which bond these two conditions are described in this focused review. The need to screen red flags for ATTR-CA in elderly patients with HFpEF is urgently advised, because a prompt recognition of the disease can optimize the approach to the disease with an early therapeutic, life-saving choice.

Maintenance therapy promotes profound organ and haematologic response in light-chain amyloidosis patients not undergoing autologous stem cell transplantation

Background Evidence on maintenance therapy following frontline induction is sparse in primary light-chain amyloidosis (AL), especially for those who do not undergo autologous haematopoietic stem cell transplantation (ASCT). Methods We enrolled primary AL patients who achieved at least haematologic very good partial response (VGPR) by the 4th month at the frontline from December 2008 to June 2023 at Zhongshan Hospital, Fudan University. Those who followed maintenance therapy were identified as the maintenance group (n = 44), whereas those entering the observational phase were classified as the observational group (n = 24). Results After 7.2(interquartile range, 4.7–18.6) months of maintenance therapy, 9(20.5%), 14(31.8%) and 5 (11.4%) patients achieved improvement in haematologic, cardiac and renal response respectively. Five (11.4%) patients had minimal residual disease (MRD) response conversion from positive to negative based on maintenance therapy. In the observation group, none of the patients had haematologic response improvement, with 3(12.5%) and 1(4.2%) patient showing cardiac and renal response improvement during follow-up. Conclusion This study identified the clinical benefits of maintenance therapy in patients with AL who did not undergo ASCT in real-world practice.

TTR associated leptomeningeal amyloidosis in a Sri Lankan patient

ObjectivesThis case report aims to contribute to the expanding genotypic-phenotypic spectrum of TTR associated leptomeningeal amyloidosis. MethodsNeuroimaging and targeted TTR Sanger sequencing were performed on a 52-year-old female presenting with cognitive and motor symptoms. ResultsThe proband, a Sri Lankan woman, presented with a gradually progressive cognitive decline, followed by a rapid deterioration in motor function and level of consciousness. She had a significant family history of an undiagnosed neurological disorder, characterized by cognitive impairment and early death occurring in the fifth decade of life. Analysis of cerebrospinal fluid (CSF) demonstrated elevated protein levels. CT scan of the brain showed extensive leptomeningeal calcifications and hydrocephalus, and gadolinium enhanced magnetic resonance imaging (MRI) demonstrated extensive leptomeningeal enhancement in the brain and spinal cord.Genetic analysis revealed c.113 A > G, p.D38G mutation in TTR, a rare mutation with characteristic clinic-radiological central nervous system features. DiscussionLeptomeningeal amyloidosis represents the least common subtype of familial transthyretin amyloidosis, which is a life-threatening condition. Among the over 150 identified mutations, few are specifically associated with central nervous system disease. The genetic spectrum and clinical phenotypes including neuroimaging findings continue to expand. It is important to maintain a high index of suspicion for leptomeningeal amyloidosis, particularly when the presentation is not acute or when there are relapsing-remitting symptoms. Consideration of family history and early genetic testing are essential to facilitate appropriate treatment and genetic counselling.

Aspects cliniques des amyloses systémiques en 2024

The three most common varieties of systemic amyloidosis are transthyretin amyloidosis (ATTR), immunoglobulin amyloidosis (AL) and inflammatory amyloidosis (AA). There are two forms of transthyretin amyloidosis: the wild type, the most common, represents approximately 15% of heart diseases and the genetic, or "mutated" form, which is a rare disease and manifests mainly by peripheral neuropathy and heart disease. Major therapeutic advances have been made in recent years thanks to molecules that stabilize transthyretin and/or prevent its translation by destroying messenger RNA. Immunoglobulin amyloidosis (AL) is a hematological disease whose severity is due to the toxicity of immunoglobulin light chains forming amyloid deposits that are toxic to tissues, particularly the heart and kidneys. Treatments for immunoglobulin amyloidosis are increasingly effective, and target the plasma cell, leading to an overall improvement in the prognosis, with cardiac involvement being the most worrying condition. Inflammatory amyloidosis (AA) complicates chronic inflammatory diseases less often due to the effectiveness of anti-inflammatory biotherapies in inflammatory rheumatism, chronic inflammatory bowel diseases and genetic auto-inflammatory diseases. The causes of inflammatory amyloidosis are now more diverse with an increase in cases of unknown cause associated or not with obesity.

Conformational Differences in the Light Chain Constant Domain of Immunoglobulin G and Free Light Chain May Influence Proteolysis in AL Amyloidosis

Immunoglobulin light chain amyloidosis (AL) is a life-threatening disease caused by the deposition of light chain (LC) and its fragments containing variable (VL) and portions of constant (CL) domains. AL patients feature either monoclonal free LCs (FLCs) circulating as covalent and noncovalent homodimers, or monoclonal immunoglobulin (Ig) wherein the LC and heavy chain (HC) form disulfide-linked heterodimers, or both. The role of full-length Ig in AL amyloidosis is unclear as prior studies focused on FLC or VL domain. We used a mammalian cell-based expression system to generate four AL patient-derived full-length IgGs, two non-AL IgG controls, and six corresponding FLC proteins derived from an IGLV6-57 germline precursor. Comparison of proteins’ secondary structure, thermal stability, proteolytic susceptibility, and disulfide link reduction suggested the importance of local vs. global conformational stability. Analysis of IgGs vs. corresponding FLCs using hydrogen–deuterium exchange mass spectrometry revealed major differences in the local conformation/dynamics of the CL domain. In all IgGs vs. FLCs, segments containing β-strand and α-helix βAC-αACBC were more dynamic/exposed while segment βDC-βEC was less dynamic/exposed. Notably, these segments overlapped proteolysis-prone regions whose in vivo cleavage generates LC fragments found in AL deposits. Altogether, the results suggest that preferential cleavage in segments βAC-αACBC of FLC or βDC-βEC of LC in IgG helps generate amyloid protein precursors. We propose that protecting these segments using small-molecule stabilizers, which bind to the interfacial cavities CL-CL in FLC and/or CL-CH1 in IgG, is a potential therapeutic strategy to complement current approaches targeting VL-VL or VL-CL stabilization of LC dimer.

Circulating ECM proteins decorin and alpha-L-iduronidase differentiate ATTRwt-CM from ATTRwt-negative HFpEF/HFmrEF.

Wild-type transthyretin cardiac amyloidosis (ATTRwt-CM) is an under-recognized aetiology of heart failure (HF), necessitating early detection for timely treatment. Our study aimed to differentiate patients with ATTRwt-CM from ATTRwt-negative HFpEF/HFmrEF patients by identifying and validating circulating protein biomarkers. In addition, we measured the same biomarkers in patients with cardiomyopathy due to light chain amyloidosis (AL)-CM to gain disease-specific insights. In this observational study, serum concentrations of 363 protein biomarkers were measured in a discovery cohort consisting of 73 ATTRwt-CM, 55 AL-CM, and 59 ATTRwt-negative HFpEF/HFmrEF patients, using multiplex proximity extension assays. Sparse partial least squares analyses showed overlapping ATTRwt-CM and AL-CM biomarker profiles with clear visual differentiation from ATTRwt-negative patients. Pathway analyses with g:Profiler revealed significantly up-regulated proteoglycans (PG) and cell adhesion pathways in both ATTRwt-CM and AL-CM. Penalized regression analysis revealed that the proteoglycan decorin (DCN), lysosomal hydrolase alpha-L-iduronidase (IDUA) and glycosyl hydrolase galactosidase β-1 (GLB-1) most effectively distinguished ATTRwt-CM from ATTRwt-negative patients (R2 = 0.71). In a prospective validation cohort of 35 ATTRwt-CM patients and 25 ATTRwt-negative patients, DCN and IDUA significantly predicted ATTRwt-CM in the initial analysis (DCN: OR 3.3, IDUA: OR 0.4). While DCN remained significant after correcting for echocardiographic parameters, IDUA did not. DCN showed moderate discriminative ability (AUC, 0.74; 95% CI, 0.61-0.87; sensitivity, 0.91; specificity, 0.52) as did IDUA (AUC, 0.78; 95% CI, 0.65-0.91; sensitivity, 0.91; specificity, 0.61). A model combining clinical factors (AUC 0.92) outperformed DCN but not IDUA, a combination of the biomarkers was not significantly better. Neither DCN nor IDUA correlated with established disease markers. ATTRwt-CM has a distinctly different biomarker profile compared with HFpEF/HFmrEF, while ATTRwt-CM patients share a similar biomarker profile with AL-CM patients characterized by up-regulation of proteoglycans and cell-adhesion pathways. The biomarkers DCN and IDUA show the potential to serve as an initial screening tool for ATTTRwt-CM. Further research is needed to determine the clinical usefulness of these and other extracellular matrix components in identifying ATTRwt-CM.

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.

Predictors of mortality by an artificial intelligence enhanced electrocardiogram model for cardiac amyloidosis.

We aim to determine if our previously validated, diagnostic artificial intelligence (AI) electrocardiogram (ECG) model is prognostic for survival among patients with cardiac amyloidosis (CA). A total of 2533 patients with CA (1834 with light chain amyloidosis (AL), 530 with wild-type transthyretin amyloid protein (ATTRwt) and 169 with hereditary transthyretin amyloid (ATTRv)] were included. An amyloid AI ECG (A2E) score was calculated for each patient reflecting the likelihood of CA. CA stage was calculated using the European modification of the Mayo 2004 criteria for AL and Mayo stage for transthyretin amyloid (ATTR). Risk of death was modelled using Cox proportional hazards, and Kaplan-Meier was used to estimate survival. Median age of the cohort was 67 [inter-quartile ratio (IQR) 59, 74], and 71.6% were male. The median overall survival for the cohort was 35.6months [95% confidence interval (CI) 32.3, 39.5]. For AL, ATTRwt and ATTRv, respectively, median survival was 22.9 (95% CI 19.2, 28.2), 47.2 (95% CI 43.4, 52.3) and 61.4 (95% CI 48.7, 75.9) months. On univariate analysis, an increasing A2E score was associated with more than a two-fold risk of all-cause death. On multivariable analysis, the A2E score retained its importance with a risk ratio of 2.0 (95% CI 1.58, 2.55) in the AL group and 2.7 (95% CI 1.81, 4.24) in the ATTR group. Among patients with AL and ATTR amyloidosis, the A2E model helps to stratify risk of CA and adds another dimension of prognostication.

Targeting high-affinity nicotinic receptors protects against the functional consequences of β-amyloid in mouse hippocampus.

The accumulation of β-amyloid oligomers is a hallmark of Alzheimer's disease, inducing neural and network dysfunction in the early stages of pathology. The hippocampus is affected early in the pathogenesis of AD, however the impact of soluble β-amyloid on the dentate gyrus (DG) subregion of the hippocampus and its interaction with nicotinic acetylcholine receptors (nAChRs) within this region are not known. Using a localized model of over-expression, we show that β-amyloid induces early-onset neuronal hyperactivity and hippocampal-dependent memory deficits in mice. Further, we find the DG region to be under potent and sub-type specific nicotinic control in both healthy and pathophysiological conditions, with targeted receptor inhibition leading to a mnemonic rescue against localized amyloidosis. We show that while neurogenesis and synaptic functions are not severely affected in our model, reducing β2-containing nAChR function is associated with the promotion of young adult-born neurons within the pathological network, suggesting a possible protective mechanism. Our data thus reveal the DG network level changes which occur in the early-stages of β-amyloid accumulation and highlight the downstream consequences of targeted nicotinic neuromodulation.

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

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. 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. 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. 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.

Epidemiology, diagnosis, and management of cardiac amyloidosis.

Cardiac amyloidosis (CA) is an infiltrative restrictive cardiomyopathy caused by the deposition of amyloid fibrils in the myocardium. It manifests in two primary subtypes: transthyretin cardiac amyloidosis (ATTR) and immunoglobulin light chain cardiac amyloidosis (AL). ATTR is further classified into wild-type and hereditary based on transthyretin gene mutation. Advances in diagnostics and therapeutics have transformed CA from a rare and untreatable condition to a more prevalent and manageable disease. Noninvasive diagnostic tools such as electrocardiography, echocardiography, and cardiac magnetic resonance can raise suspicion for CA; bone scintigraphy can non-invasively confirm ATTR, while AL necessitates histological confirmation. The severity of ATTR and AL can be assessed through serum biomarker-based staging. Treatment approaches differ, ranging from silencing or stabilizing transthyretin and degrading amyloid fibrils in ATTR to employing anti-plasma cell therapies and autologous stem cell transplantation in AL.

The effect of topical tranexamic acid with micro-needling and micro-needling alone in treatment of macular amyloidosis.

Macular amyloidosis is a form of primary localized cutaneous amyloidosis presented by pruritic pigmented macules in rippled or reticulate pattern. The aim of this study was to assess the efficacy of using topical tranexamic acid with micro-needling comparing to micro-needling alone in patients with macular amyloidosis. Patients with bilaterally located macular amyloidosis on trunk or upper extremities were recruited in this trial. The skin lesions in all patients were divided into two parts which were randomly assigned to the group of treatment with micro-needling plus tranexamic acid and the group of micro-needling alone. There were four sessions of treatment with 2 weeks interval. The percentage of improvement in pigmentation (based on photographs and dermoscopy) and rippling of each group was determined by three blinded dermatologists. The level of patient satisfaction and reduction of pruritus was measured by a questionnaire and defined as a percentage. Twenty females were enrolled in this study. The mean (SD) patients' age was 39.7 (±10.13) years. Both groups showed improvement in pigmentation based on images, dermoscopy, and rippling pattern. Patients' satisfaction was 46.5% in tranexamic acid group and 47.5% in micro-needling alone. Nevertheless, there was no significant difference between both groups (p value >0.05). Interestingly, the pruritus improved 61.66% after four sessions of treatment in both groups. Micro-needling is a suitable modality for decreasing pruritus and pigmentation in macular amyloidosis. However, topical application of tranexamic acid does not lead to additional improvement.