Search Results (194)

Cardiac amyloidosis (CA) is an infiltrative cardiomyopathy caused by extracellular deposition of misfolded proteins, most commonly immunoglobulin light chains (AL) or transthyretin (ATTR). Once considered a rare disease, CA is increasingly recognised due to improved diagnostic strategies and the availability of disease-modifying therapies. Early diagnosis is crucial, as treatment efficacy and clinical outcomes are strongly influenced by the stage of cardiac involvement. Multimodality cardiac imaging plays a central role in the diagnostic pathway, risk stratification, and evaluation of therapeutic response in CA. Echocardiography represents the first-line imaging modality and is essential for raising clinical suspicion through the identification of characteristic structural and functional abnormalities, including ventricular wall thickening, diastolic dysfunction, and distinctive strain patterns. Bone scintigraphy has revolutionised the non-invasive diagnosis of ATTR-CA, allowing accurate identification of transthyretin-related disease in the absence of monoclonal gammopathy, which needs to be excluded via serum and urinary immunofixation. Cardiovascular magnetic resonance provides advanced tissue characterisation through late gadolinium enhancement and quantitative mapping techniques, enabling detection of early myocardial involvement and robust prognostic stratification. Emerging imaging modalities, including dual-energy (spectral) computed tomography and positron emission tomography tracers, show promise in myocardial amyloid quantification and subtype differentiation, although their role is still evolving. Integration of imaging findings with clinical and laboratory parameters allows comprehensive disease assessment, facilitating early diagnosis, guiding therapeutic decisions, and improving risk stratification. This review summarises the current role of multimodality imaging in CA, highlighting its contribution from early detection to prognostic evaluation and monitoring of treatment efficacy, with particular emphasis on the emerging role of quantitative imaging in monitoring treatment response. Full article

Transthyretin cardiac amyloidosis (ATTR-CA) is an increasingly recognized cause of cardiac dysfunction in adults, resulting from extracellular deposition of misfolded transthyretin fibrils and progressive myocardial impairment. Clinical expression and diagnostic yield differ substantially between sexes, contributing to systematic underdiagnosis in women, who often present with subtler myocardial remodeling, heart failure with preserved ejection fraction (HFpEF)–dominant phenotypes, and nonspecific systemic manifestations that fall below conventional diagnostic thresholds, particularly in early disease stages. Female patients, particularly those with ATTRwt, tend to present at older ages and more frequently show HFpEF-dominant phenotypes and nonspecific extracardiac manifestations. Carpal tunnel syndrome (CTS) is an important extracardiac red flag for ATTR-CM, but its interpretation in women requires caution because of the high background prevalence of idiopathic CTS in the general population. Evidence also suggests sex-related differences in diastolic function, right ventricular involvement, and overall progression. Despite these biological and phenotypic distinctions, women are markedly underrepresented in trials of disease-modifying therapies, limiting conclusions about sex-specific treatment effects and leaving uncertainty about whether current pharmacologic interventions provide comparable benefit. Hormonal influences, genetic background, and age-related mechanisms, comorbidities, and diagnostic pathways may contribute to the distinctive female phenotype, but underlying mechanisms remain insufficiently defined. This narrative review examines sex-associated differences in ATTR-CA, focusing on mechanisms of underdiagnosis, principal clinical and imaging features, and implications for therapeutic response, with the goal of improving diagnostic accuracy, guiding individualized management, and ultimately enhancing outcomes for women and all affected patients worldwide in clinical practice. Full article

Background and Objectives: Amyloidosis is a systemic disorder characterized by extracellular deposition of misfolded protein fibrils, most commonly light-chain (AL) or transthyretin-derived (ATTR) ones. Cardiac involvement is well recognized, but large-vessel complications, including thoracic aortic aneurysms (TAA) and dissections, are rare and under-reported. The aim of this review article is to provide insights into pathophysiology, clinical diagnosis and the therapeutic opportunities in amyloidosis-related thoracic aortic diseases. Methods and Materials: The PRISMA Extension for Scoping Reviews (PRISMA-ScR) Guidelines were followed. An extensive search of the available literature in the English language, published between 1 January 2000, and 31 December 2025, in three large-scale scientific databases was undertaken by two independent reviewers. The terms “amyloidosis”, “thoracic aorta”, “thoracic aortic aneurysm”, “aortic dissection”, and “aortopathy” were used both as specific items, as well as in MeSH Terms. Studies reporting on the pathophysiology, diagnosis, clinical manifestations, treatment options and prognosis of amyloid deposition on the thoracic aorta were included in the review. Because of the nature of the existing literature, only a narrative review was possible. Results: Twenty-nine studies were included. Owing to the rarity of reporting, data was derived mainly from case reports and series, as well as autopsy studies. Amyloid infiltration of the aortic wall has been associated with medial architectural disruption, degeneration of elastic fibers, impairment of vasa vasorum perfusion, and arterial stiffness, all of which could contribute to aneurysmal dilation and aortic lesions. Amyloidosis management combines targeted anti-plasma cell therapy with supportive care. In AL amyloidosis, melphalan–dexamethasone (MDex) was historically standard, but regimens such as cyclophosphamide, bortezomib, and dexamethasone (CyBorD) and bortezomib, melphalan, and dexamethasone (BMDex) achieve higher complete response rates. Immunotherapy with Daratumumab has shown high overall and complete response rates. Fibril-directed approaches, including doxycycline and epigallocatechin gallate, and monoclonal antibodies, are under evaluation. Acute management of large-vessel manifestations follows conventional protocols, but prognosis is often dominated by underlying cardiac and systemic involvement. Conclusions: Management of thoracic aortic involvement follows standard imaging surveillance and surgical criteria, though operative risk is increased. Multidisciplinary care, early recognition, and individualized risk stratification are essential to improve outcomes, particularly given frequent cardiac involvement. Full article

Light chain (AL) amyloidosis is a systemic disorder caused by plasma cell dyscrasia, with cardiac involvement being the primary determinant of prognosis. Survival outcomes vary significantly across disease stages. This heterogeneity underscores a critical need for early diagnosis, precise risk stratification, and response-adapted therapy. In this context, multimodality imaging has emerged as an indispensable non-invasive tool, providing crucial insights for clinical decision-making. This review synthesizes recent advances in the application of key imaging modalities—echocardiography, magnetic resonance imaging, and nuclear medicine imaging—for evaluating AL amyloidosis. We highlight how these techniques have shifted the paradigm from anatomical assessment to quantitative, multiparametric tissue characterization, ultimately guiding personalized patient management. Full article

Background: In low-flow, low-gradient aortic stenosis (LFLG AS), restricted aortic valve opening may represent either fixed valvular obstruction or flow-dependent incomplete leaflet opening due to reduced forward flow. Aortic stenosis (AS) and transthyretin cardiac amyloidosis (ATTR-CM) may coexist, making it difficult to distinguish myocardial disease–driven low-flow physiology from clinically relevant valvular obstruction. Case Presentation: An 88-year-old man presented with decompensated heart failure and paradoxical LFLG AS. Dobutamine stress echocardiography (DSE) failed to restore normal flow, and the calculated aortic valve area remained within the severe range despite stress. Computed tomography showed a low aortic valve calcium score (AVCS) of 313 Agatston units, leaving true-severe versus pseudo-severe AS indeterminate. Further evaluation confirmed wild-type ATTR-CM. Because the contribution of AS to heart failure was uncertain, the patient was initially managed with optimized heart failure therapy. Approximately two years later, he was readmitted with recurrent acute decompensated heart failure, severe left ventricular systolic dysfunction, dobutamine dependency, end-organ congestion, and a classical LFLG AS phenotype. Although AS severity remained indeterminate, a clinically relevant valvular afterload component could not be excluded. At that time, tafamidis was not immediately available because of local access limitations. Because left ventricular assist device implantation and heart transplantation were not feasible and surgical aortic valve replacement carried prohibitive risk, transcatheter aortic valve implantation (TAVI) was performed after discussion by the Heart Team. Left ventricular ejection fraction improved early after TAVI, from 19.9% before the procedure to 29.4% at 3 days and 44.1% at 35 days. At 1-year follow-up, left ventricular ejection fraction remained improved at 51%, and more than two years after TAVI, the patient continues regular outpatient follow-up without recurrent heart failure hospitalization. Conclusions: In ATTR-CM with LFLG AS, DSE and AVCS may not definitively determine AS severity. Carefully selected TAVI, combined with ATTR-directed and optimized heart failure therapy, may be associated with early left ventricular functional recovery and sustained clinical improvement. Full article

Daratumumab, a human IgG1 monoclonal antibody targeting CD38, is widely used in multiple myeloma and AL amyloidosis. Despite its clinical success, many patients fail to achieve durable responses or relapse, underscoring the importance of understanding resistance mechanisms. Drawing on experience from other better-studied monoclonal antibodies, resistance to daratumumab can be categorized into four main mechanisms: (1) reduced CD38 expression on plasma cells; (2) increased expression of complement inhibitory proteins (CD55/CD59), impairing complement-mediated cytotoxicity; (3) reduced drug bioavailability due to urinary loss in non-selective nephrotic syndrome; and (4) the development of neutralizing anti-daratumumab antibodies. Anti-drug antibodies (ADAs) may represent a potential mechanism of treatment failure through effects on pharmacokinetics, efficacy, and safety, even in patients on daratumumab therapy. Seven different trials have tested anti-daratumumab antibodies. Among them, anti-daratumumab antibodies were identified in only 0–2.4% of patients, and only in a small portion of these has it been proven to be neutralizing. Overall, ADAs appear rare, but these findings are likely underestimated due to short follow-up and suboptimal timing of assessment. In conclusion, standardized ADA monitoring, particularly months after treatment interruption or in cases of inadequate response or infusion-related reactions, may improve patient management and therapeutic outcomes. Full article

Cardiomyopathies are traditionally classified by structural and genetic phenotypes, but emerging evidence highlights chronic myocardial inflammation as a pivotal driver of disease progression across different etiologies. This review synthesizes the current literature on the cellular and molecular inflammatory mechanisms underlying hypertrophic cardiomyopathy, Anderson–Fabry disease, cardiac amyloidosis, arrhythmogenic cardiomyopathy, and dilated cardiomyopathy. Across these distinct conditions, endogenous triggers such as metabolic substrates, misfolded amyloid fibrils, mechanical stress, or viral genomes act as damage-associated molecular patterns. These stimuli activate innate and adaptive immune cascades, notably the Toll-like receptors, the NF-κB pathway, and the NLRP3 inflammasome. This immune activation establishes a pro-inflammatory microenvironment that promotes fibroblast reprogramming, myocardial edema, and progressive fibrotic or fibro-fatty remodeling. Inflammation is an active, core pathophysiological mechanism rather than a passive secondary bystander in cardiomyopathies. Recognizing these shared immune pathways provides a framework for improved risk stratification and highlights the potential for targeted immunomodulatory therapies to alter disease trajectories. Full article

Physiotherapy is an evidence-based healthcare occupation aiming to collaborate in the diagnosis, prevention and treatment of a myriad of diseases and clinical scenarios throughout all stages of human life. Its development has been accelerated over the last two decades. The scope of physiotherapy is continuously evolvig. However, the accumulated evidence in the context of rare diseases is scarce. Remarkably, the opportunity for improvement and potential benefit for complex diseases with low prevalence is also very high, both as an isolated approach or within multidisciplinary specialized units. Systemic light-chain (AL) amyloidosis is a rare, chronic, complex, heterogeneous, incurable, and challenging disease, which may involve different organs and systems, including the heart, kidney, liver, peripheral nerves, lung, muscle, skin, and others. Heart is the most frequently involved organ leading to failure and arrhythmias. Peripheral neuropathy is a relatively frequent symptom. Renal, respiratory, and hepatic failure may also occur. The aim of this narrative review is summarizing, updating, and critically underlining potential new avenues of development on the role of physiotherapy in systemic light-chain (AL) amyloidosis, compared with its application in multiple myeloma, a closely related but not so rare entity. Full article

Background: Advances in diagnostic criteria for transthyretin cardiac amyloidosis (ATTR-CM) and expanded insurance coverage for bone scintigraphy have facilitated earlier detection of ATTR-CM. However, whether these changes have translated into improved clinical outcomes among patients receiving disease-modifying therapy remains uncertain, especially in non-high-volume centers. Methods: Consecutive patients with ATTR-CM who started disease-modifying therapy at our institute between May 2019 and March 2025 were retrospectively analyzed. Baseline characteristics and clinical outcomes were compared between the early period (2019–2021) and the late period (2021–2025). Results: A total of 31 patients (median age 77 years, 77% male) were included. Duration of heart failure was significantly shorter and the dose of loop diuretics at baseline was significantly lower in the late period (p < 0.05 for both). The prevalence of National Amyloid Center (NAC) stage I at baseline tended to be higher in the late period (75.0% versus 53.5%, p = 0.273). The cumulative incidence of worsening heart failure hospitalization and all-cause death was significantly lower in the late period (6.3% versus 44.2%, p = 0.024) during a median follow-up of 5 years. NAC stage I at baseline was independently associated with the lower primary outcome with an adjusted hazard ratio of 0.10 (95% confidence interval 0.01–0.90, p = 0.040). Conclusions: Patients with ATTR-CM in the late group experienced more favorable clinical outcomes after disease-modifying therapy, probably due to earlier diagnosis and therapeutic intervention, although further studies are warranted to verify the hypothesis. Full article

Background: AF in the setting of cardiac amyloidosis is associated with a high risk of TEs, irrespective of CHA2DS2-VASc score. While warfarin has been the traditional anticoagulant, DOACs offer a promising alternative, but their safety in this population remains underexplored. This study aimed to evaluate the prevalence of thromboembolic events (TEs), including stroke and transient ischemic attack (TIA), and major bleeding events in patients with cardiac amyloidosis (CA) and atrial fibrillation (AF) treated with either warfarin or direct oral anticoagulants (DOACs). Additionally, we aimed to explore whether DOACs are at least as effective as warfarin in protecting against TEs in this population. Methods: This retrospective cohort study analyzed 422 patients with confirmed CA and AF from Mayo Clinic, with a median follow-up of 4.3 years. Data on anticoagulation therapy, baseline characteristics, and outcomes (TEs and bleeding) were collected. Statistical analyses included chi-square tests, t-tests, and Cox regression to assess the relationship between anticoagulation and TE. Results: Among 422 patients, 21 experienced a TE. The annual event rate was 0.83% for warfarin and 0.67% for DOACs, with no significant difference (HR 0.66, CI 0.22–2.01, p = 0.5). Patients with anticoagulation interruptions > 5 days had increased TE risk (HR 3.19, CI 0.97–10.5, p = 0.056). The bleeding rate was 9.9% over 4.3 years (2.33% per year), with no significant differences between anticoagulants. Conclusions: Both warfarin and DOACs have similar, low risks of TEs in CA and AF patients. However, anticoagulation interruptions were associated with increased TE risk, emphasizing the challenges in managing anticoagulation in this population. Full article

Background: Crohn‘s disease (CD) is frequently complicated by extraintestinal manifestations, including axial spondyloarthritis (axSpA). Both diseases share genetic (HLA-B27, IL23R, ERAP1/2) and immunopathological mechanisms (Th17/IL-23 axis). Their co-occurrence increases the risk of systemic complications such as AA amyloidosis. Case presentation: We report a 42-year-old male with HLA-B27-positive axSpA who developed CD shortly after initiating secukinumab (IL-17A inhibitor). Following discontinuation of secukinumab and surgical management of CD, the patient experienced rapidly progressive AA amyloidosis affecting the kidneys and intestines, leading to acute kidney injury and requiring hemodialysis. Potential triggering factors included a preceding intestinal infection and self-administered infrared physiotherapy. Conclusions: Coexistent CD and axSpA significantly increases the risk of severe AA amyloidosis. IL-17 inhibitors should be used with extreme caution in patients with subclinical or active CD. Early screenings for proteinuria and low-threshold biopsy are essential to detect AA amyloidosis. In patients with both conditions, TNF-α or IL-12/23 inhibitors are preferred over IL-17 blockade. Full article

Relapsing polychondritis (RP) is a rare autoimmune disease of cartilaginous structures, often diagnosed late due to nonspecific presentations. Both RP and granulomatosis with polyangiitis (GPA) can cause diffuse tracheobronchial wall thickening on computed tomography (CT) and may be seronegative for anti-neutrophil cytoplasmic antibody (ANCA), creating a diagnostic impasse. We report a 46-year-old man with two months of fever, productive cough, and sternal pain. A saddle nose deformity was the only cartilaginous sign; serum ANCA was repeatedly negative. Neck CT showed diffuse tracheal and bilateral main bronchial wall thickening; the report listed amyloidosis and GPA as differential diagnoses, omitting RP. Despite laboratory, microbiological, and imaging workup, the fever fulfilled criteria for fever of unknown origin (FUO), prompting ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT. PET/CT demonstrated intense FDG uptake in the cartilaginous wall of the tracheobronchial tree, forming the classic inverted-Y sign, with bilateral costal cartilage hypermetabolism (a site not involved in GPA) and no uptake in the kidneys, sinuses, or orbits, collectively establishing a diagnosis of RP. Corticosteroid therapy elicited prompt clinical and biochemical response. This case demonstrates that ¹⁸F-FDG PET/CT can differentiate RP from GPA when CT and serology are uninformative. Full article

Background/Objectives: AA amyloidosis is a serious complication of chronic inflammation, which may arise in the setting of inborn errors of immunity (IEIs) due to recurrent or persistent infections. Common variable immunodeficiency (CVID) is the most frequent symptomatic IEI in adults, yet its association with secondary AA amyloidosis remains rarely reported. Case presentation: We describe a 37-year-old male with a history of recurrent pneumonia, chronic sinusitis, and osteomyelitis with sepsis since childhood. At age 33, he developed bilateral pneumonia after COVID-19, followed by repeated lower respiratory tract infections. At age 36, nephrotic syndrome (proteinuria 10.69 g/day, hypoalbuminemia) led to kidney and gastric mucosa biopsies, which confirmed AA amyloidosis. Immunological workup revealed panhypogammaglobulinemia (IgG 0.1 g/L, IgA 0.01 g/L, IgM 0.28 g/L), markedly reduced switched memory B cells, and an inverted CD4⁺/CD8⁺ ratio. Chest CT showed bronchiectasis, bronchiolitis, and mediastinal lymphadenopathy. Whole-exome sequencing excluded known monogenic IEIs, autoinflammatory, or hereditary amyloidosis genes; a heterozygous likely pathogenic variant in ODAD2 (associated with primary ciliary dyskinesia) was considered incidental. A diagnosis of CVID with secondary AA amyloidosis was established. Conclusions: This case illustrates that CVID may remain undiagnosed for decades and present with secondary AA amyloidosis as the first major complication. In any patient with nephrotic syndrome and a history of recurrent or unusual infections, an IEI should be actively excluded. Early recognition of CVID and appropriate immunoglobulin replacement therapy can prevent infectious exacerbations and potentially halt amyloid progression. Full article

Transthyretin (TTR) amyloidosis is a systemic, progressive, and fatal disease. TTR is integral in vitamin A (retinol) transport via its binding to retinol binding protein 4 (RBP4). Current and emerging therapies for TTR amyloid cardiomyopathy (ATTR-CM), including RNAi therapies and potentially CRISPR-based therapies, reduce hepatic transthyretin production and hence decrease serum RBP4, which decreases circulating vitamin A levels. However, despite these reductions in circulating vitamin A, hepatic reserves and alternative delivery mechanisms may prevent clinical manifestations of vitamin A deficiency. Vitamin A functions as a key regulator of immunity, antioxidant function, cell growth and differentiation and vision. This paper aims to serve as a comprehensive review of vitamin A and its metabolites, their transport, and their function in human health and disease. Additionally, we seek to synthesize the relevant outcomes and safety data of TTR silencing therapies and how they relate to circulating vitamin A levels and vitamin A-related clinical outcomes in a manner that is relevant to the cardiac amyloidosis specialist. Full article

The liver produces the majority of plasma proteins, maintaining the metabolic homeostasis. The dysregulation of liver protein synthesis underlies many systemic conditions. Therefore, there is a great potential in therapies that inhibit the hepatic protein production. This is the mechanism of action of antisense oligonucleotides (ASOs) and small interfering RNA (siRNA). These therapeutics have undergone rapid development and are revolutionizing the pharmacological landscape of many liver-related diseases (e.g., inclisiran in familial hypercholesterolemia). Furthermore, gene-editing technologies that allow a direct correction of impaired genes in the liver are currently being evaluated. They hold a promise for future advances in treatment, especially of monogenic disorders such as hereditary transthyretin amyloidosis or alpha-1 antitrypsin deficiency. In this review, we describe the most relevant systemic diseases caused by dysfunction of protein synthesis in liver cells, in which significant therapeutic progress has been made over the last decades. Moreover, we present currently available drugs and their mechanisms of action, including six siRNA agents and five ASOs that have been approved to date. Finally, we discuss emerging strategies, focusing on novel RNA-based therapeutics that are the subjects of ongoing clinical trials. Full article