Search Results (53)

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: Early diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM) remains challenging. Although ECG and morphological abnormalities at diagnosis are well-described, their temporal evolution has not been systematically evaluated. This study characterized the prevalence and longitudinal progression of electrical and structural cardiac abnormalities preceding ATTR-CM diagnosis. Methods: We retrospectively analyzed patients with confirmed ATTR-CM evaluated at a specialist amyloidosis center between 2006 and 2023. Diagnosis was established by grade 2–3 myocardial uptake on 99mTc-DPD scintigraphy. Standard 12-lead ECGs and transthoracic echocardiograms were reviewed at diagnosis and at baseline, 3–5 years earlier. Results: Sixty-three patients (79% men; mean age 77 ± 8 years) were studied, including 33 (52%) with hereditary ATTR (ATTRv) and 30 (48%) with wild-type ATTR (ATTRwt). Overall, 95% had a NAC score ≤ 2, consistent with less advanced disease at diagnosis. During the prediagnostic phase, 79% of patients exhibited pathological ECGs. Non-specific ST–T abnormalities (40%), prolonged QTc (38%), left-axis deviation (35%), first-degree AV block (33%) and anterior infarction pattern (33%) were each observed in at least one-third of patients. From baseline to diagnosis, significant prolongation was observed in the PR interval (+26 ms), QRS duration (+11 ms), and QTc interval (+22 ms) (p < 0.001 for all), and a leftward shift observed in the electrical axis (−12.03°, p = 0.011). Low voltage was uncommon at both time points. Although interventricular septal thickness increased significantly (+3.42 mm; p < 0.001), left ventricular ejection fraction and dimensions were relatively stable. Conclusions: In this proof-of-concept study, electrical remodeling precedes functional changes and outperforms low voltages to raise clinical suspicion of ATTR-CM. Full article

Background/Objectives: Hereditary transthyretin amyloidosis (ATTRv) is a heterogeneous multisystem disease caused by pathogenic transthyretin gene (TTR) variants. Increased awareness and availability of disease-modifying therapies have resulted in increased diagnoses, even in previously nonendemic regions. The aim of this study was to update the nationwide Austrian ATTRv registry by characterizing the clinical, genetic, and regional distribution of TTR variants. Methods: This multicenter, observational analysis examined ATTRv cases diagnosed in Austria between 2014 and 2025. Individuals were included according to the presence of pathogenic or likely pathogenic variants or variants of uncertain significance (VUSs) in TTR. Results: In total, 100 individuals were identified, including symptomatic and asymptomatic carriers. Compared with our previously presented data, the number of genetically confirmed ATTRv cases has more than doubled. Twenty-three TTR variants were identified. The most frequent pathologic variants were p.His108Arg (26%), p.Ile127Phe (11%), and p.Thr69Ile (9%), while p.Val113Leu (9%) represented the most frequent VUS. Significant regional clustering of p.His108Arg was documented in Vienna and Lower Austria. Other findings included a rising number of p.Val142Ile carriers and phenotypically relevant VUSs in 20 patients. Conclusions: Our findings revealed an increasing detection rate of ATTRv in a nonendemic European region. These data underscore the importance of multidisciplinary evaluation, cascade testing, and long-term monitoring to improve early diagnosis and timely management in hereditary amyloidosis. 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

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

In transthyretin cardiac amyloidosis (ATTR-CA), misfolded transthyretin accumulates in the myocardium, leading to wall thickening and interstitial fibrosis. Recently published in vitro studies revealed direct effects of transthyretin on the structure, function, and gene expression of cardiac fibroblasts. Therefore, we hypothesized that biomarkers known to modulate myocardial remodeling might be clinically valuable in ATTR-CA and may improve risk stratification in ATTR-CA. To analyze this hypothesis, we evaluated 14 fibrosis-related biomarkers (EN-RAGE, IGFBP-1, -2, -3, -4, -6, FGF-23, MMP-2, -7, -9, -13, TIMP-2, -4, and RAGE-AGE) in 125 patients using Luminex multiplex assays. The study cohort consists of 14 asymptomatic gene carriers (ATTRv-asymp), 47 symptomatic hereditary (ATTRv-CA), 43 wild-type Transthyretin amyloidosis (ATTRwt) patients, and 21 were healthy controls (ctrl). Associations of fibrotic biomarkers and clinical routine data with clinical outcomes—cardiac decompensation (DMP) and transplantation/death (HTX)—were assessed via hierarchical cluster analysis, regression, and prediction modeling. We found that ATTR-CA patients showed distinct biomarker profiles compared to controls. Several markers (e.g., MMP-7, RAGE-AGE, IGFBP-1, FGF-23, TIMP-2) were significantly associated with both endpoints. Cluster analysis identified a high-risk phenotype (Cluster 2) with worse renal function, greater myocardial thickening, and elevated NT-proBNP, hsTNT. Prediction modeling revealed IGFPB-1, -3, -4 and -6 as well as FGF-23, TIMP-2, and RAGE/AGE as the best predictive parameters for cluster assignment. Taken together, these findings confirm our hypothesis that fibrosis-related biomarkers are associated with adverse outcomes in ATTR-CM. Profibrotic mediators such as IGFBP-1, FGF-23, and TIMP-2 may, therefore, provide additional prognostic information beyond established cardiac biomarkers and may reflect underlying fibrotic remodeling pathways. Full article

Background/Objectives: Hereditary transthyretin amyloidosis (ATTRv) is an autosomal dominant disorder characterized by systemic deposition of amyloid fibrils, leading to peripheral neuropathy and multisystemic involvement. Peripheral nerve ultrasound is a promising tool for detecting structural nerve changes, yet its use in Latin American populations is limited. This study aimed to characterize nerve ultrasound findings in Brazilian patients with ATTRv. Methods: We conducted a cross-sectional study of 72 genetically confirmed ATTRv individuals from two Brazilian centers. Participants were classified into symptomatic patients with polyneuropathy (n = 31) and asymptomatic TTR variant carriers (n = 41). All participants underwent a standardized neurological examination, and nerve ultrasound was used to assess the median nerve, brachial plexus, and C6 root. Cross-sectional areas (CSAs) from the right side were used for analysis and compared to reference values. Results: Symptomatic patients showed increased CSAs in the median nerve (wrist: 10.17 mm², arm: 9.8 mm²), C6 root (8.55 mm²), and brachial plexus (70.82 mm²; all p < 0.05), but not in the forearm. Notably, asymptomatic carriers exhibited nerve enlargement in the median nerve at the wrist, the C6 root, and the brachial plexus, despite lacking clinical signs of neuropathy. Peripheral nerve enlargement in ATTRv affects both symptomatic patients and asymptomatic carriers, with a predilection for proximal and entrapment sites. Conclusions: These findings support the utility of nerve ultrasound as a non-invasive biomarker for early nerve involvement in ATTRv. Further studies are warranted to validate its role in disease monitoring and guide therapeutic interventions, especially in genetically at-risk populations. Full article

This review article aims to provide an overview of the pathophysiology, diagnosis, and contemporary management of cardiac amyloidosis (CA) as well as identify the knowledge gaps and areas of potential research. CA can be divided into two main groups: transthyretin cardiac amyloidosis (ATTR-CA) and light chain cardiac amyloidosis (AL-CA). The former further separates into wild-type transthyretin (ATTRwt) and hereditary transthyretin (ATTRv). African Americans, males, and people older than 75 are the most common demographics affected by this disease. Thanks to an increased understanding of this disease combined with better diagnostic techniques, there is growing awareness and a surge of clinical trials aimed at improving outcomes of CA. The diagnosis and treatment of CA is multifaceted and complex, relying on multiple imaging modalities and the cooperation of specialists to deliver effective treatments. While some disease-modifying agents have been introduced recently, their extraordinary cost limits their benefit or they are supported by limited evidence. Other agents are currently undergoing phase 3 trials. To date, there is scarce data surrounding optimal diagnostic and treatment strategies, including a potential role for combination therapies. Critically, it is imperative that physicians develop close relationships with the patient that addresses not only their individual health needs but also their unique psychosocial situation. Therefore, more clinical trials, protocols and patient resources are needed to better inform and guide providers managing these complex patient needs. Full article

Background/Objectives: Hereditary transthyretin amyloidosis (ATTRv) is a progressive and fatal disease with >130 known underlying variants in the TTR gene. We describe the utility of two no-charge genetic testing programs in identifying TTR variants in participants across Europe/Middle East and North America, respectively. Methods: Eligible adult participants in GeneAct^® and Alnylam Act^® had a family history or clinical suspicion of ATTRv. Testing was performed using gene panels for neuropathies or cardiomyopathy, or a single-gene TTR test. Diagnostic yield was defined as one pathogenic/likely pathogenic variant in TTR. Results: Overall, 2713 and 89,760 participants were tested in GeneAct^® and Alnylam Act^®. Genetic diagnosis was established in 95 and 4297 participants, respectively, resulting in a diagnostic yield of 3.5% and 4.8%. V122I (p.V142I) was the most common variant, identified in 34 of these participants in GeneAct^® and 3299 in Alnylam Act^®. Cardiac and neurologic signs/symptoms were the most common manifestations across both programs, as reflected in the specialties ordering tests in Alnylam Act^® (cardiology, 29.1%; neurology, 31.5%). Conclusions: These data highlight the importance of genetic testing for early identification of ATTRv, especially among patients with cardiac and neuropathy symptoms. Genetic testing has the potential to improve diagnostic timeframes and outcomes in ATTRv. Full article

Background: Hereditary transthyretin amyloidosis (ATTRv) is a rare, autosomal dominant multisystem disease caused by pathogenic variants in the transthyretin (TTR) gene. Although ATTRv is classically categorized into “cardiac” and “neurologic” phenotypes, recent evidence suggests a more complex and overlapping disease spectrum. Objectives: This study investigates the relationship between neurological staging and cardiac involvement through an integrated assessment of patients with confirmed TTR mutations. Methods and Results: Fifty-eight patients with genetically confirmed ATTRv (41% female, mean age 60 ± 15 years) were evaluated. Genotypes included Phe64Leu, Val30Met, Val122Ile, and others. Patients were stratified by neurological stage: G0 (asymptomatic carriers), G1 (symptomatic but ambulatory), and G2 (requiring walking support). Cardiac assessment included clinical evaluation, echocardiography with tissue Doppler, global longitudinal strain (GLS), and NT-proBNP levels. Cardiac markers worsened with neurological stage. NT-proBNP, left ventricular mass index, maximal wall thickness, and E/E′ ratio increased progressively, while GLS declined (G0: –19%, G1: –14%, G2: –13%; p < 0.001), indicating a progressive structural and functional myocardial disease. Ejection fraction remained preserved. Neurological stage independently predicted cardiac dysfunction after age adjustment. Conclusions: This is the first study to assess cardiac abnormalities across neurological stages in a well-characterized cohort of ATTRv patients. Cardiac involvement in ATTRv begins early, even in asymptomatic carriers, and progresses with neurological deterioration. GLS and diastolic parameters are sensitive indicators of early myocardial dysfunction, highlighting the need for integrated neurologic and cardiac monitoring in all patients with ATTRv, regardless of initial phenotype. Full article

Background: Hereditary transthyretin amyloidosis (ATTRv) is a systemic disorder caused by homozygosity or compound heterozygosity for pathogenic mutations in the TTR gene, leading to destabilization of the transthyretin tetramer, misfolding of monomers, and subsequent amyloid fibril deposition. Among over 150 known TTR variants, p.Val142Ile is particularly associated with late-onset cardiac involvement and is the most prevalent amyloidogenic mutation in individuals of African and, to a lesser extent, European descent. This study reports the identification and familial segregation of the p.Val142Ile mutation in a large multigenerational family from Calabria (Southern Italy). Methods: Genomic DNA was extracted from peripheral blood, and Sanger sequencing of the TTR gene was performed in the proband and extended family. Results: The proband was a 75-year-old man with clinical features suggestive of cardiac amyloidosis. Genetic testing revealed homozygosity for the TTR p.Val142Ile variant. Family screening revealed multiple heterozygous carriers across three generations, most of whom were asymptomatic. Discussion: This is the first report of a native Calabrian family carrying this variant, previously unreported in this region, where p.Phe84Leu was considered the only endemic TTR mutation. Our findings expand the mutational landscape of ATTRv in Southern Italy and highlight the presence of p.Val142Ile in a previously unrecognized geographic area. These results reinforce the importance of including TTR sequencing in the work-up of unexplained cardiomyopathy, particularly in Southern Italy, where atypical variants may be emerging. Full article

Transthyretin-related (ATTR) amyloidosis is a progressive, multisystem disease caused by the extracellular deposition of misfolded transthyretin (TTR) monomers as insoluble amyloid fibrils. Clinical manifestations vary widely and may include cardiomyopathy (ATTR-CM), polyneuropathy (ATTR-PN), or mixed phenotypes. The condition is increasingly recognized as an underdiagnosed contributor to heart failure, particularly in elderly patients. ATTR amyloidosis exists in two major forms: hereditary (ATTRv), resulting from mutations in the TTR gene, and wild-type (ATTRwt), typically affecting men over 70 years of age. Advances in disease understanding have led to a paradigm shift in management, with the introduction of targeted therapies that slow disease progression and improve prognosis. First-generation therapies such as tafamidis have demonstrated survival benefits in ATTR-CM. More recently, second-generation agents—such as the TTR stabilizer acoramidis and RNA silencers including vutrisiran and eplontersen—have shown promising efficacy in clinical trials. Additional strategies under investigation include gene editing and monoclonal antibodies targeting TTR amyloid deposits. This review outlines current diagnostic strategies and therapeutic options for ATTR amyloidosis, emphasizing the need for early detection and individualized treatment approaches. The expanding therapeutic landscape highlights the importance of accurate phenotyping and timely intervention to optimize clinical outcomes. Full article

Hereditary transthyretin amyloidosis (ATTRv) is an autosomal dominant disorder caused by pathogenic variants in the TTR gene. The destabilized mutant form of the transport protein transthyretin (TTR) leads to the extracellular deposition of amyloid fibrils. Materials and Methods: A 65-year-old female patient with suspected clinical diagnosis of ATTR was referred for genetic testing for pathogenic variants in the TTR gene after physical, neurological and cardiac testing. Results: The patient had had cardiac dysfunction, atrial fibrillation and supraventricular tachycardia for around 10 years before the suspected and confirmed cardiac amyloidosis. The molecular genetic testing showed a heterozygous pathogenic variant in exon 3 of the TTR gene NM_000371.4(TTR): c.258A>C, p.(Glu86Asp). This variant in the TTR gene is classified as pathogenic in accordance with ACMG/AMP for the interpretation of variants. Conclusions: The presented case of a very rare pathogenic variant in the TTR gene displays the valuable role of genetic testing on the way to clarifying a diagnosis. Full article

Transthyretin (TTR) variant (V30M) polyneuropathy (ATTRv-PN) is a progressive systemic amyloidosis caused by transthyretin aggregation, leading to a variety of debilitating manifestations, including neuropathy and cardiomyopathy. We investigated the plasma proteome of heterozygotic V30M TTR asymptomatic carriers and heterozygotic V30M ATTRv-PN patients (before and after tafamidis treatment) versus WT TTR healthy control plasma using an organic solvent-induced shift in solubility assay to identify biosignatures for disease progression and therapeutic response. We identified many proteins, including TTR, apolipoproteins, ceruloplasmin, and proteins with functions in innate immunity that displayed changes in either their abundances or their sensitivity to precipitation. Elevated oxidative modifications of TTR and APOE in ATTRv-PN patients suggest a role for oxidative stress in disease pathogenesis/progression. Tafamidis treatment mitigated these pathology-associated changes, suggesting that alleviating proteotoxic stress impacts these other pathways. Although our study was limited to a Portuguese cohort, these findings nevertheless provide a comprehensive plasma proteomic profile of V30M ATTRv-PN patients, V30M TTR carriers, and tafamidis-treated ATTRv-PN patients over up to 60 months; provide insights into ATTRv-PN pathophysiology; identify potential biomarkers for disease progression and therapeutic response; and highlight the utility of proteomics in advancing personalized treatments for amyloidosis. Full article

Over 150 transthyretin (TTR) mutations have been identified in hereditary transthyretin (ATTRv) amyloidosis, and new TTR variants have recently emerged. However, the pathogenicity of several new variants remains unclear, making it important to elucidate the differences between amyloidogenic and wild-type TTR. In this study, we report a novel TTR variant (V121A) identified in two unrelated amyloidosis patients aged > 60 years who developed cardiomyopathy. We evaluated the detailed biochemical features of this TTR variant to confirm its amyloidogenicity using plasma samples from these patients and recombinant TTR proteins. While the V121A TTR variant has a similar ability to assemble into a tetramer as wild-type TTR, it aggregates more readily over a wide potential hydrogen range than wild-type TTR. Additionally, the V121A variant is highly prone to dissociation and resistant to binding with known TTR tetramer stabilizers. Clinical and biochemical data suggest that this novel variant is clearly pathogenic, is highly prone to dissociation and aggregation, and is associated with the development of late-onset amyloid cardiomyopathy. Interestingly, amyloid fibril formation due to this variant may not be affected by known TTR stabilizers. Full article