Search Results (161)

Deposits of insoluble protein plaques, which are mostly composed of fibrils from disease-specific amyloid proteins, are histological markers of various human disorders. These range from non-neuropathic amyloidosis such as light chain amyloidosis or type II diabetes to well-known neuro-degenerative diseases such as Alzheimer’s Disease and Parkinson’s Disease. There are indications that these types of fibrillar suprastructures display biological activity distinct from the individual fibrils they are composed of. Yet, little is known about the mechanisms underlying the assembly of fibrillar suprastructures. An understanding of secondary fibril self-assembly into mesoscopic and macroscopic suprastructures is also critical for their application as novel biomaterial. The paucity of experimental data and theoretical models on fibrillar supra-assembly likely relates to the experimental and conceptual challenges in following this type of assembly on multiple length- and timescales, and in characterizing the distinct morphologies formed. Here, we report that the amyloid dye thioflavin T (ThT) is augmented during self-assembly of isolated lysozyme fibrils. We provide evidence that this augmentation of ThT fluorescence results from the unquenching of fibril-bound ThT during fibril binding. Combining ThT fluorescence, optical density, and fluorescence quenching kinetics with optical and electron microscopy, we propose that fibril self-assembly is driven by a transition from reaction-limited ordered assembly to diffusion-limited random cross-linking of fibrils. Full article

Cellular protein quality control comprises the ubiquitin proteasome system, autophagy, and molecular chaperones, which maintain proteostasis in healthy tissues. The failure of these cellular and molecular pathways, which normally safeguard the proteome, can cause and even exacerbate amyloidoses, the abnormal accumulation of proteins into amyloid fibrils that drive neurodegeneration. Amyloidoses can also damage peripheral organs; examples include light chain amyloidosis, cardiac amyloidosis, and renal amyloidosis. Restoring proteostasis and preventing protein aggregation is therefore an active area of research, with several promising strategies under investigation. Among these approaches, small-molecule modulators that restore proteostasis are attractive candidates because they may simultaneously rescue multiple quality control mechanisms and remodel aggregates to improve their accessibility to endogenous degradation pathways. Here, we propose that amyloid pathology disrupts multiple proteostasis pathways simultaneously, creating a feedforward cascade in which the breakdown of interconnected proteostasis networks drives progressive protein aggregation, which in turn propels proteostasis collapse. Pharmacological interventions targeting protein aggregation offer opportunity to rescue interconnected proteostasis networks, which could, in turn, cooperatively manage or eliminate pathogenic amyloid burden. Full article

Among cardiac storage diseases, amyloidosis has emerged as a common cause of heart failure (HF), particularly in older people: it is diagnosed in up to 13–19% of patients with heart failure and preserved ejection fraction. Current treatments for transthyretin amyloidosis (ATTR) focus on stopping the misfolding of the TTR protein or reducing TTR production and treating the symptoms with cardiac medication, while systemic chemotherapy is the focus for light-chain amyloidosis (AL). New fibril clearance agents and gene therapies are currently in development. In addition to clinical and laboratory observations, multimodal imaging is essential for the monitoring of the effects of treatment on the progression of heart disease, but it is not yet included in established staging systems. This narrative review collects current multimodal imaging parameters that have been evaluated in clinical trials to assess the progression of cardiac amyloidosis and used in phase III intervention studies. These evolving findings are compared with current consensus recommendations to identify gaps in knowledge for specific imaging modalities, particularly cardiac MRI. Ultimately, the goal should be to standardize imaging of disease progression in cardiac amyloidosis so that the therapeutic effects of new pharmacological treatment options can be compared with the current standard of care. Full article

Background: Thrombosis in light chain amyloidosis (LCA) occurs in the context of multiple organ dysfunction and inflammation. Conventional coagulation tests (screening) may not sufficiently capture the procoagulant substrate in the inflammatory/therapeutic dynamics. Methods: A total of 61 consecutive patients with LCA were prospectively included in the study. Clinical data, including organ involvement, time of diagnosis, treatment phase, DOAC exposure and thrombosis history were systematically recorded and subjected to screening. Specialized hemostasis tests such as APTT/PT, fibrinogen, D-dimer, TEG and TGT were performed and conventional times were analyzed in the subgroup without DOAC. Results: The prevalence of documented thrombosis was 32.8%, and thrombosis status was associated with TEG positivity and more strongly with TGT positivity. Hypercoagulability was identified in 50.8% by TEG and 41.0% by TGT, regardless of whether APTT/PT were within the reference values. APTT/PT did not predict thrombosis recurrence (p > 0.05), which was predicted by TEG (p = 0.0027) and TGT (p = 0.0006). An inflammation/fibrin turnover panel (CRP, fibrinogen, D-dimer) predicted TEG positivity (p < 0.0001), but not TGT, and was correlated with assessment at diagnosis, daratumumab-based therapy, and cardiac involvement. Conclusions: Global tests (TEG/TGT) promptly correlate with thrombosis recurrence in our cohort and provide crucial information in addition to clotting times for thrombotic phenotyping. Inflammation can influence TEG, so the decision to recommend the tests and the timing of their performance should be adapted to the clinical, biological, and therapeutic context. Full article

Background: Cardiac amyloidosis (CA) is an increasingly recognized cause of heart failure with preserved ejection fraction, resulting from myocardial deposition of misfolded amyloid fibrils derived predominantly from transthyretin (ATTR wild-type [ATTRwt] or variant [ATTRv]) or immunoglobulin light chains (AL). Despite advances in noninvasive imaging and disease-modifying therapies, delayed diagnosis remains common, and clinically actionable molecular biomarkers for early detection, phenotypic discrimination, and therapeutic monitoring are limited. MicroRNAs (miRNAs), small noncoding regulators of post-transcriptional gene expression, have emerged as key modulators of cardiovascular remodeling and systemic amyloid biology. Methods: We performed a comprehensive review of experimental, translational, and clinical studies to evaluate the role of miRNAs in transthyretin and light-chain cardiac amyloidosis, incorporating data from myocardial tissue analyses, circulating miRNA profiling, and mechanistic studies in cellular and animal models. Results: Dysregulated miRNA networks contribute to amyloid-induced cardiac injury by modulating mitochondrial energetics, oxidative stress, inflammation, fibrosis, proteostasis, and neurocardiac signaling. Specific miRNAs, including members of the miR-21, miR-29, and miR-30 families, as well as miR-150-5p and miR-339, have been associated with amyloid burden, adverse myocardial remodeling, plasma cell biology, and disease severity. Distinct circulating and tissue miRNA signatures differentiate transthyretin from light-chain cardiac amyloidosis and correlate with functional status, heart failure biomarkers, and clinical outcomes. Conclusions: MiRNAs represent promising diagnostic and prognostic biomarkers in cardiac amyloidosis and offer mechanistic insights into disease pathogenesis. Integration of miRNA profiling with multimodality imaging and emerging RNA-based therapeutics may enable earlier diagnosis and support precision management of amyloid-related heart failure. Full article

Background/Objectives: Serum neurofilament light chain (sNfL) is a biomarker for peripheral neuropathy as sNfL correlates with polyneuropathy severity in hereditary transthyretin (ATTRv) amyloidosis. It is unclear whether sNfL also correlates with autonomic neuropathy (ANP). In this exploratory study, we aimed to evaluate the value of sNfL as marker for ANP in patients with ATTRv amyloidosis. Methods: sNfL was measured retrospectively in 10 pathogenic transthyretin gene variant (TTRv) carriers and 28 patients with ATTRv amyloidosis. All 38 individuals underwent a comprehensive evaluation for ANP. Results: Individuals with ANP had a higher median sNfL level compared to those without ANP (p < 0.001). In univariable logistic regression analysis, age-adjusted sNfL status (normal versus abnormal for age) was associated with sex, ANP, and peripheral neuropathy. In multivariable logistic regression analysis, only peripheral neuropathy significantly predicted age-adjusted sNfL status (normal versus abnormal for age), and no signal was detected for ANP. Receiver operating characteristic analysis showed a considerable area under the curve for ANP. However, the confidence interval was wide for both analyses and only four cases with isolated ANP were included. Conclusions: Therefore, in this exploratory cohort, sNfL could not be identified as a marker for ANP, and larger studies are needed to clarify its value. Full article

Light-chain (AL) amyloidosis is a rare and incurable disease, classified under the category of plasma cell neoplasms and other diseases with paraproteins in the 5th Edition of the World Health Organization classification of lymphoid tumors. This entity shares some similarities with multiple myeloma (MM), remarkably a bone marrow infiltration of clonal plasma cells. Moreover, one out of five newly diagnosed cases of AL amyloidosis (NDAL) also fulfills the current diagnostic criteria for MM. A multidisciplinary therapy approach should be established, in which hematological therapy plays a crucial role. Anti-clonal therapy is the basis of hematological therapy, in addition to supportive therapy and emerging anti-fibrils therapy. In recent years, advances in the anti-clonal therapy for MM have progressively transferred to carefully selected patients with systemic AL amyloidosis, significantly improving outcomes in this rapidly changing field. This review aims to critically analyze the comparative evolution and evidence-based approach of anti-clonal therapy in NDAL vs. MM since the introduction of bortezomib. Participation in clinical trials remains the first option to consider in daily clinical practice. Full article

Background/Objectives: Serum neurofilament light chain (sNfL) is an early and sensitive biomarker of polyneuropathy. This study compared the UmanDiagnostics enzyme-linked immunosorbent assay (ELISA), and Meso Scale Discovery (MSD) R-PLEX assay with the current gold-standard single-molecule array (Simoa) assay for sNfL measurement. Methods: sNfL levels were measured with Simoa, ELISA, and MSD R-PLEX in 330 serum samples from 73 individuals with a pathogenic transthyretin gene variant (TTRv) and in 165 healthy controls (HC) with ELISA and MSD R-PLEX. Results: Median sNfL levels, assessed in serum samples from TTRv individuals, differed across all assays (all p < 0.001). Passing–Bablok regression slopes were 1.01 (Simoa–ELISA), 1.00 (Simoa–MSD R-PLEX), and 1.02 (MSD R-PLEX-ELISA), with very strong correlations (all r > 0.8). Bland–Altman analysis showed mean differences of 0.1 ± 0.2 pg/mL (Simoa–ELISA), 0.7 ± 0.1 pg/mL (Simoa–MSD R-PLEX), and −0.6 ± 0.2 pg/mL (MSD R-PLEX-ELISA). In HC, sNfL levels positively correlated with age. Z-score normalization allowed for inter-assay comparison. Conclusions: The ELISA and MSD R-PLEX assays provide suitable alternatives for the Simoa assay to measure sNfL levels in carriers of a pathogenic TTR-gene variant. The differences in concentrations defined by the assays directly relate to the internal standard provided with the assays. Full article

Introduction: Cardiac amyloidosis, primarily comprising transthyretin amyloid cardiomyopathy (ATTR-CM) and light-chain amyloidosis with cardiac involvement (AL-cardiac), is an increasingly recognized contributor to the global heart failure burden. Management has shifted from supportive care to disease-modifying agents targeting specific stages of the amyloid cascade. This registry-based review qualitatively characterizes the current pharmacological clinical trial landscape through a registry-based analysis. Methods: A structured qualitative analysis of ClinicalTrials.gov was conducted for interventional trials registered between January 2015 and November 2025. Following PRISMA principles, studies were screened to include pharmacological interventions with explicit cardiac targeting while excluding neuropathy-dominant amyloidosis. Trial-level data regarding therapeutic classes, study phases, enrollment, and primary outcome domains were extracted and synthesized. Results: A total of 18 trials met the inclusion criteria (14 ATTR-CM; 4 AL-cardiac), representing a total enrollment of 4924 participants across 11 unique agents. Five therapeutic classes were identified: amyloid-clearing monoclonal antibodies (44.4% of trials), TTR silencers, TTR stabilizers, fibril-modifying agents, and cardiac phenotype-directed therapies. Monoclonal antibodies represented the largest class by both trial count and enrollment (3075 participants). Clinical events (n = 7) and safety/tolerability (n = 5) were the most frequent primary outcome domains. ATTR-CM trials dominated the landscape, accounting for 77.7% of the total study population, while parallel-group placebo-controlled designs were the most common study architecture (n = 10). Conclusions: The therapeutic landscape for cardiac amyloidosis is transitioning toward stage-specific, mechanism-based interventions. While ATTR-CM currently dominates research efforts, the expansion of silencers and monoclonal antibodies reflects an increasing capacity to intercept the amyloid cascade at distinct molecular checkpoints. However, significant heterogeneity in outcome measures and the shift toward diagnosing milder disease pose challenges for demonstrating clinical efficacy. Future priorities include standardized progression markers and addressing barriers to global access for these high-cost therapies. Full article

Background: Common variable immunodeficiency (CVID) is the most frequent symptomatic primary antibody deficiency, associated with recurrent infections, immune dysregulation, and non-infectious complications. Amyloidosis is a rare but severe complication with pulmonary involvement being exceptional. Objective: The aim of this study was to review reported cases of amyloidosis complicating CVID and present a unique case of pulmonary involvement. Methods: A literature research identified observational studies and case reports linking amyloidosis with CVID. Additionally, we describe a patient with CVID complicated by pulmonary and gastrointestinal amyloidosis. Results: Fifteen cases were identified, mostly amyloid A (AA) with multiple organ involvement. Only one case of pulmonary amyloidosis was reported. To date, no cases of pulmonary light-chain amyloidosis (AL) have been described in CVID patients without an underlying plasma cell dyscrasia. Our patient initially presented with AA amyloidosis but evolved to systemic AL type with rapid progression and fatal outcome despite therapy. Conclusions: Amyloidosis should be considered in CVID patients with atypical symptoms. Accurate amyloid typing is essential as treatment differs between AA and AL types. Early recognition may improve outcomes. Full article

Cardiac amyloidosis is an infiltrative cardiomyopathy caused by extracellular deposition of misfolded proteins, most commonly immunoglobulin light chains (AL) or transthyretin (ATTR), with rarer forms occurring less frequently. AL amyloidosis arises from plasma cell-derived light chains and typically follows an aggressive clinical course, whereas ATTR amyloidosis results from misfolded wild-type or variant transthyretin and progresses more indolently. Extracellular vesicles (EVs) have recently been recognized as mediators of amyloid propagation, inflammation, and myocardial remodeling, particularly at later stages of disease. Despite growing evidence, no comprehensive reviews have focused on this relationship. We conducted a structured narrative review (PubMed and Scopus, 2020–2025) following Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines to synthesize emerging data. EVs act as scaffolds for transthyretin and serum amyloid A aggregation and carry disease-specific protein and RNA cargo detectable in blood and urine. Experimental models also demonstrate EV-mediated transport of serum amyloid A under conditions of cardiac stress, representing a reactive amyloidogenic pathway rather than a common cause of human cardiac amyloidosis. Preclinical studies show regenerative and anti-fibrotic effects of stem-cell-derived EVs, and early clinical trials demonstrate the feasibility of EV-based cardiac therapy. While methodological and translational challenges persist, EVs represent promising diagnostic and therapeutic tools that could transform the precision management of cardiac amyloidosis. Full article

Background: Cardiac amyloidosis is characterized by progressive myocardial and atrial infiltration, leading to atrial mechanical dysfunction, atrial fibrillation, and thromboembolic complications. Left atrial (LA) strain is an established marker of atrial function; however, data on triplane LA strain in cardiac amyloidosis are limited. Methods: We evaluated transthoracic echocardiographic examinations of 24 patients with cardiac amyloidosis and 24 age-, sex-, rhythm-, and ejection fraction-matched control subjects (9 with atrial fibrillation in each group). Among amyloidosis patients, 21 had transthyretin and 3 had light-chain cardiac amyloidosis. All examinations were performed during 2025. Triplane and biplane LA reservoir strain were assessed using speckle-tracking echocardiography. Two-way analysis of variance tested the effects of disease (amyloidosis vs. control) and rhythm (sinus rhythm vs. atrial fibrillation). Agreement between triplane and biplane measurements was evaluated using Pearson correlation and Bland–Altman analyses. Results: Triplane LA reservoir strain was significantly lower in patients with cardiac amyloidosis compared with controls (6.7 ± 2.7% vs. 16.2 ± 8.3%, p < 0.001). Even in sinus rhythm, amyloidosis patients demonstrated markedly impaired LA strain, with mean values similar to those observed in control subjects with atrial fibrillation. Two-way ANOVA revealed significant main effects of disease (F = 68.9, p < 0.0001) and rhythm (F = 45.0, p < 0.0001), as well as a significant disease–rhythm interaction (F = 26.5, p < 0.0001). Triplane and biplane LA strain showed strong correlation (r = 0.90, p < 0.0001) with good agreement. Reproducibility was excellent (intra-observer ICC = 0.97; inter-observer ICC = 0.94). Conclusions: Triplane LA reservoir strain is markedly reduced in cardiac amyloidosis and enables comprehensive visualization of atrial mechanical dysfunction. The technique demonstrates high reproducibility and strong agreement with biplane analysis, supporting its use as a complementary tool for characterizing amyloid atriopathy. Full article

Amyloidosis is a group of disorders caused by extracellular deposition of insoluble fibrillar proteins, leading to progressive organ dysfunction. Cardiac amyloidosis is clinically significant, as myocardial infiltration results in restrictive cardiomyopathy, arrhythmias, and heart failure. The main subtypes are light-chain (AL) and transthyretin (ATTR) amyloidosis, while AA and isolated atrial amyloidosis (IAA) are less common. Accurate subtype identification is crucial for management and prognosis. Diagnosis requires a multimodal approach combining imaging and tissue-based techniques. Echocardiography is usually first-line, showing increased wall thickness, biatrial enlargement, and apical sparing. Cardiac magnetic resonance (CMR) provides superior tissue characterization through late gadolinium enhancement and elevated extracellular volume. Nuclear scintigraphy with 99mTc-labeled tracers enables non-invasive ATTR detection, while amyloid-specific PET tracers show potential for early diagnosis. Histochemical confirmation remains essential. Congo Red staining with apple-green birefringence under polarized light is the diagnostic gold standard, supported by Thioflavin T, PAS, and Alcian Blue stains. Immunohistochemistry and mass spectrometry aid amyloid typing, while electron microscopy provides ultrastructural confirmation. Integrating imaging, histochemical, immunohistochemical, and proteomic techniques enhances early recognition and precise classification, improving therapeutic strategies and patient outcomes. Full article

Low QRS voltage relative to left ventricle (LV) thickness is one of the red flag characteristics in the diagnosis of cardiac amyloidosis, and it can be measured by specific indexes. Few studies have clearly defined the diagnostic threshold of voltage indexes for light chain amyloidosis cardiomyopathy (AL-CA) patients and other patients with LV hypertrophy. This case–control study analyzed electrocardiograms and echocardiograms of patients with AL-CA, hypertrophic cardiomyopathy (HCM), and hypertension left ventricular hypertrophy (HTN-LVH) seen at a single university center from 2008 to 2022. Low QRS voltage and three different precordial voltage indexes were evaluated. Diagnostic thresholds for rule-in and rule-out were calculated for AL-CA against each control group. A single voltage–mass ratio based on cross-sectional area (CSA) exhibited most accurate diagnostic accuracy, and the value of ≤1.72 aids the rule-in of AL-CA against other causes of left ventricular hypertrophy, providing a positive predictive value (PPV) of 86% versus HCM and 75% versus HTN-LVH. Full article

Background/Objectives: Transthyretin cardiomyopathy (ATTR-CM) is frequently associated with conduction disease requiring pacing. Conventional right ventricular pacing may worsen cardiac function, whereas left bundle branch area pacing (LBBAP) aims to preserve physiological activation. Evidence for LBBAP in ATTR-CM remains limited. Methods: A structured narrative review of PubMed and Google Scholar was performed through November 2025 using predefined terms related to LBBAP and ATTR-CM. Peer-reviewed articles, case reports, case series, and relevant abstracts were included. Studies exclusively on light-chain cardiac amyloidosis were excluded. Results: Ten publications met inclusion criteria, comprising three case reports, five case series, one retrospective cohort without a comparator, and one cohort comparing LBBAP with cardiac resynchronization therapy (CRT). In total, 56 patients with ATTR-CM underwent LBBAP. Implantation success was high, with stable acute and mid-term electrical parameters. Follow-up (typically 3–12 months) showed stable electrical parameters with narrow paced QRS complexes and preserved or improved left ventricular ejection fraction in most reports. Symptomatic improvement and reductions in natriuretic peptides were variably described. No major lead-related complications were reported. Comparative data remain sparse and inconclusive. Conclusions: This review suggests that LBBAP is a feasible and safe pacing approach in patients with ATTR-CM and may help to stabilize or improve heart failure symptoms. Further prospective studies are needed to confirm its clinical effectiveness. Full article