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Medicina Clinica May 2024Tafamidis is the only approved transthyretin stabiliser approved for the treatment of variant transthyretin amyloidosis (A-ATTRv) related polyneuropathy (PNP). The aim...
INTRODUCTION
Tafamidis is the only approved transthyretin stabiliser approved for the treatment of variant transthyretin amyloidosis (A-ATTRv) related polyneuropathy (PNP). The aim of this study is to analyse the effectiveness of tafamidis in a real-world setting in Spain.
METHODS
This is a national multicenter study in which patients with V30M A-ATTR related PN treated with tafamidis for at least 1 year were included. Clinical, demographic, analytical and neurophysiological variables were analysed.
RESULTS
100 patients were recruited. Overall, 47 patients (47%) were classified as complete responders, 32 (32%) as partial responders and 21 (21%) as non-responders. The median duration of treatment with tafamidis was 35 months. Better treatment response was shown in patients with in polyneuropathy disability score (PND) I, lower neuropathy impairment score (NIS), compound muscle action potential (CMAP) and Norfolk QoL questionnaire. Higher albumin levels and lower NTproBNP levels were also associated with better treatment response. A basal NIS≥15 predicts that the patient could be a non-responder with a 60% probability.
CONCLUSIONS
Our results reinforce the tafamidis efficacy to treat A-ATTRv-PNP if started early in the disease course. Patients with the V30M variant, NIS<15 and PND I are the most appropriate subjects for this treatment.
Topics: Humans; Male; Female; Benzoxazoles; Amyloid Neuropathies, Familial; Spain; Aged; Middle Aged; Polyneuropathies; Treatment Outcome; Prealbumin; Aged, 80 and over; Peptide Fragments
PubMed: 38556397
DOI: 10.1016/j.medcli.2024.01.008 -
International Journal of Molecular... Mar 2024Trigonelline (TRG) is a natural polar hydrophilic alkaloid that is found in many plants such as green coffee beans and fenugreek seeds. TRG potentially acts on multiple... (Review)
Review
Trigonelline (TRG) is a natural polar hydrophilic alkaloid that is found in many plants such as green coffee beans and fenugreek seeds. TRG potentially acts on multiple molecular targets, including nuclear factor erythroid 2-related factor 2 (Nrf2), peroxisome proliferator-activated receptor γ, glycogen synthase kinase, tyrosinase, nerve growth factor, estrogen receptor, amyloid-β peptide, and several neurotransmitter receptors. In this review, we systematically summarize the pharmacological activities, medicinal properties, and mechanistic actions of TRG as a potential therapeutic agent. Mechanistically, TRG can facilitate the maintenance and restoration of the metabolic homeostasis of glucose and lipids. It can counteract inflammatory constituents at multiple levels by hampering pro-inflammatory factor release, alleviating inflammatory propagation, and attenuating tissue injury. It concurrently modulates oxidative stress by the blockage of the detrimental Nrf2 pathway when autophagy is impaired. Therefore, it exerts diverse therapeutic effects on a variety of pathological conditions associated with chronic metabolic diseases and age-related disorders. It shows multidimensional effects, including neuroprotection from neurodegenerative disorders and diabetic peripheral neuropathy, neuromodulation, mitigation of cardiovascular disorders, skin diseases, diabetic mellitus, liver and kidney injuries, and anti-pathogen and anti-tumor activities. Further validations are required to define its specific targeting molecules, dissect the underlying mechanistic networks, and corroborate its efficacy in clinical trials.
Topics: Humans; NF-E2-Related Factor 2; Alkaloids; Diabetes Mellitus; Oxidative Stress
PubMed: 38542359
DOI: 10.3390/ijms25063385 -
The Journal of Biological Chemistry May 2024Aggregation of leukocyte cell-derived chemotaxin 2 (LECT2) causes ALECT2, a systemic amyloidosis that affects the kidney and liver. Previous studies established that...
Aggregation of leukocyte cell-derived chemotaxin 2 (LECT2) causes ALECT2, a systemic amyloidosis that affects the kidney and liver. Previous studies established that LECT2 fibrillogenesis is accelerated by the loss of its bound zinc ion and stirring/shaking. These forms of agitation create heterogeneous shear conditions, including air-liquid interfaces that denature proteins, that are not present in the body. Here, we determined the extent to which a more physiological form of mechanical stress-shear generated by fluid flow through a network of narrow channels-drives LECT2 fibrillogenesis. To mimic blood flow through the kidney, where LECT2 and other proteins form amyloid deposits, we developed a microfluidic device consisting of progressively branched channels narrowing from 5 mm to 20 μm in width. Shear was particularly pronounced at the branch points and in the smallest capillaries. Aggregation was induced within 24 h by shear levels that were in the physiological range and well below those required to unfold globular proteins such as LECT2. EM images suggested the resulting fibril ultrastructures were different when generated by laminar flow shear versus shaking/stirring. Importantly, results from the microfluidic device showed the first evidence that the I40V mutation accelerated fibril formation and increased both the size and the density of the aggregates. These findings suggest that kidney-like flow shear, in combination with zinc loss, acts in combination with the I40V mutation to trigger LECT2 amyloidogenesis. These microfluidic devices may be of general use for uncovering mechanisms by which blood flow induces misfolding and amyloidosis of circulating proteins.
Topics: Humans; Amyloid; Intercellular Signaling Peptides and Proteins; Kidney; Stress, Mechanical; Amyloid Neuropathies; Shear Strength; Renal Plasma Flow; Protein Aggregates
PubMed: 38537700
DOI: 10.1016/j.jbc.2024.107231 -
Revista de La Facultad de Ciencias... Mar 2024The most common form of hereditary amyloidosis is associated with variants of transthyretin (TTR). Familial amyloidosis polyneuropathy associated with variants of TTR...
INTRODUCTION
The most common form of hereditary amyloidosis is associated with variants of transthyretin (TTR). Familial amyloidosis polyneuropathy associated with variants of TTR (FAP-TTR) is an infrequent, multisystemic disease, with predominant involvement of the peripheral nervous system. More than 130 pathogenic variants have been identified so far and most of them are amyloidogenic, being Val30Met the most frequently described.
CASE REPORT
A 74 year-old male was evaluated for progressive decreased sensitivity and associated loss of strength in four limbs in the previous two years, needing assistance for walking. Areflexia, bilateral tibialis anterior and gastrocnemius atrophy, bilateral anesthesia and apalesthesia were found in lower limbs. Bilateral hypoesthesia was reported in upper limbs. No painful dysesthesia, hyperalgesia or allodynia were found. DNA sequencing of the TTR gene led to the detection of the variant c.186G>C in heterozygous state. The resulting variant (Glu62Asp), located in the critical functional domain, has not been published before.
CONCLUSION
The importance of considering late onset, sporadic FAP-TTR as a differential diagnosis of cryptogenic polyneuropathy is highlighted.
Topics: Aged; Humans; Male; Amyloid Neuropathies, Familial; Prealbumin
PubMed: 38537102
DOI: 10.31053/1853.0605.v81.n1.40992 -
Circulation Journal : Official Journal... Jun 2024The prevalence of transthyretin amyloid cardiomyopathy (ATTR-CM) in atrial fibrillation (AF) patients remains unclear. We explored the efficacy of computed...
Efficacy of Computed Tomography-Based Evaluation of Myocardial Extracellular Volume Combined With Red Flags for Early Screening of Concealed Cardiac Amyloidosis in Patients With Atrial Fibrillation.
BACKGROUND
The prevalence of transthyretin amyloid cardiomyopathy (ATTR-CM) in atrial fibrillation (AF) patients remains unclear. We explored the efficacy of computed tomography-based myocardial extracellular volume (CT-ECV) combined with red flags for the early screening of concealed ATTR-CM in AF patients undergoing catheter ablation.Methods and Results: Patients referred for AF ablation at Oita University Hospital were prescreened using the red-flag signs defined by echocardiographic or electrocardiographic findings, medical history, symptoms, and blood biochemical findings. Myocardial CT-ECV was quantified in red flag-positive patients using routine pre-AF ablation planning cardiac CT with the addition of delayed-phase cardiac CT scans. Patients with high (>35%) ECV were evaluated using technetium pyrophosphate (Tc-PYP) scintigraphy. A cardiac biopsy was performed during the planned AF ablation procedure if Tc-PYP scintigraphy was positive. Between June 2022 and June 2023, 342 patients were referred for AF ablation. Sixty-seven (19.6%) patients had at least one of the red-flag signs. Myocardial CT-ECV was evaluated in 57 patients because of contraindications to contrast media, revealing that 16 patients had high CT-ECV. Of these, 6 patients showed a positive Tc-PYP study, and 6 patients were subsequently diagnosed with wild-type ATTR-CM via cardiac biopsy and genetic testing.
CONCLUSIONS
CT-ECV combined with red flags could contribute to the systematic early screening of concealed ATTR-CM in AF patients undergoing catheter ablation.
Topics: Humans; Atrial Fibrillation; Male; Female; Aged; Middle Aged; Amyloid Neuropathies, Familial; Cardiomyopathies; Catheter Ablation; Myocardium; Tomography, X-Ray Computed; Early Diagnosis
PubMed: 38522901
DOI: 10.1253/circj.CJ-23-0948 -
Cardiology and Therapy Jun 2024Transthyretin amyloidosis (ATTR) is a progressive, heterogeneous rare disease manifesting as ATTR polyneuropathy (ATTR-PN), ATTR cardiomyopathy (ATTR-CM), or a mixed...
INTRODUCTION
Transthyretin amyloidosis (ATTR) is a progressive, heterogeneous rare disease manifesting as ATTR polyneuropathy (ATTR-PN), ATTR cardiomyopathy (ATTR-CM), or a mixed phenotype. Tafamidis meglumine (20 mg po qd) is approved in some markets to delay neurologic progression in ATTR-PN, while high-dose tafamidis (80/61 mg po qd) is approved worldwide to reduce cardiovascular mortality and cardiovascular-related hospitalization in ATTR-CM. The objective of this study was to assess the real-world benefit of high-dose tafamidis for delaying neurologic progression in patients with mixed-phenotype variant ATTR-CM (ATTRv-CM).
METHODS
This exploratory, retrospective, observational cohort study evaluated anonymized electronic medical records and included adult patients with mixed-phenotype ATTRv-CM treated with high-dose tafamidis for at least 6 months. Neurologic assessments included the Medical Research Council (MRC) Scale for Muscle Strength, Neuropathy Impairment Score (NIS) muscle weakness subscale, and Polyneuropathy Disability (PND) instrument. Modified body mass index (mBMI) was also assessed.
RESULTS
Patients (N = 10) started tafamidis treatment an average of 3.8 months after diagnosis, with an average treatment duration of 20.8 months. Seven of 10 patients demonstrated normal muscle strength on the MRC scale throughout the study, and 9 of 10 patients had no decline in muscle strength during the post-treatment period. The NIS muscle weakness subscale score was ≤ 60 for all patients in the study at all time points, suggesting normal function to mild impairment. Six of 10 patients had no change in walking capacity as measured by the PND instrument at pre- and post-assessments, while one-third of patients had a decrease in PND stage (signaling improvement) from pre- to post-assessment. mBMI remained relatively stable throughout the study.
CONCLUSION
This is the first real-world study to demonstrate the potential value of high-dose tafamidis for delaying neurologic disease progression in patients with mixed-phenotype ATTRv-CM. The findings underscore the importance of multidisciplinary assessment for patients with ATTR amyloidosis.
TRIAL REGISTRATION
ClinicalTrials.gov: NCT05139680.
PubMed: 38521883
DOI: 10.1007/s40119-024-00362-9 -
The International Journal of... Jun 2024Cardiac amyloidosis (CA)-mostly transthyretin-related (ATTR-CA)-has recently gained interest in cardiology. Bone scintigraphy (BS) is one of the main screening tools for...
Cardiac amyloidosis (CA)-mostly transthyretin-related (ATTR-CA)-has recently gained interest in cardiology. Bone scintigraphy (BS) is one of the main screening tools for ATTR-CA but also used for various other reasons. The objective was to evaluate whether all CA cases are detected and what happens during follow-up. All routine BS performed at the Maastricht University Medical Center (May 2012-August 2020) were screened for the presence of CA. Scans performed for suspected CA were excluded. A Perugini stage ≥1 was classified as positive necessitating further examination. The electronic medical record system was evaluated for any contact with cardiology or other specialists until 2021. Of the 2738 BS evaluated, 40 scans (1.46%; median age 73.5 [IQR: 65.8-79.5], 82.5% male) were positive (Perugini grade 1: 31/77.5%, grade 2: 6/15%, grade 3: 3/7.5%); the potential diagnosis ATTR-CA was not seen in 38 patients (95%) by the nuclear medicine specialist. During follow-up, 19 out of those 40 patients (47.5%) underwent cardiac evaluation without diagnosing CA. Available echocardiograms of patients with a positive BS showed left ventricular hypertrophy, a preserved ejection fraction, and diastolic dysfunction ≥2 in 9/47%, 10/53%, and 4/21% of patients, respectively. Additionally, 20 (50%) patients presented to at least one specialty with symptoms indicative of cardiac amyloidosis. The prevalence of a positive BS indicating potential CA in an unselected population is low but substantial. The majority was not detected which asks for better awareness for CA of all involved specialists to ensure appropriate treatment and follow-up.
Topics: Humans; Male; Aged; Female; Predictive Value of Tests; Amyloid Neuropathies, Familial; Cardiomyopathies; Radionuclide Imaging; Radiopharmaceuticals; Netherlands; Retrospective Studies; Bone and Bones; Aged, 80 and over; Time Factors
PubMed: 38520623
DOI: 10.1007/s10554-024-03085-z -
Archivos de Cardiologia de Mexico 2024Aortic stenosis (AS) is currently the most common valvular disease, with an estimated prevalence of over 4% in octogenarians.
BACKGROUND
Aortic stenosis (AS) is currently the most common valvular disease, with an estimated prevalence of over 4% in octogenarians.
OBJECTIVE
To describe the prevalence of moderate-severe aortic stenosis (AS) in patients with wild type transthyretin amyloidosis (ATTRwt). Also, describe the clinical features, echocardiographic characteristics and clinical evolution.
METHOD
Retrospective cohort of patients with diagnosis of ATTRwt, belonging to Hospital Italiano de Buenos Aires Institutional Amyloidosis Registry, from 30/11/2007 to 31/05/2021. Patients follow up was carried out through the institution clinical history. The prevalence of moderate-severe AE was estimated and presented as a percentage with its 95% confidence interval (95% CI). The characteristics were compared by groups according to whether or not they had moderate-severe AS.
RESULTS
104 patients with ATTRwt were included. Median follow up was 476 days [interquartile range: 192-749]. Moderate-severe AS prevalence at the ATTRwt time of diagnosis was 10.5% (n = 11; 95% CI: 5-18%). The median age of patients with AS moderate-severe at the time of diagnosis of ATTRwt was 86 years [78-91] and the male sex predominated (82%). Most of the patients had a history of heart failure (n = 8) and atrial fibrillation (n = 8) prior to the diagnosis of ATTRwt. Most of the patients were subclassified as low flow low gradient severe AS group (n = 7). Four patients underwent some intervention on the aortic valve. During follow-up, 5 patients (46%) were hospitalized for decompensated heart failure and 4 (36%) died.
CONCLUSIONS
In our cohort, the coexistence of both pathologies had a similar prevalence as reported in the international literature. It was an elderly population with a high percentage of atrial fibrillation and history of heart failure. Most of the patients presented with severe AS with low flow low gradient.
Topics: Aged, 80 and over; Humans; Male; Aged; Retrospective Studies; Atrial Fibrillation; Prevalence; Amyloid Neuropathies, Familial; Heart Failure; Aortic Valve Stenosis
PubMed: 38507302
DOI: 10.24875/ACM.22000074 -
The Israel Medical Association Journal... Mar 2024Cardiac amyloidosis (CA) is characterized by the extracellular deposition of misfolded protein in the heart. Precise identification of the amyloid type is often...
BACKGROUND
Cardiac amyloidosis (CA) is characterized by the extracellular deposition of misfolded protein in the heart. Precise identification of the amyloid type is often challenging, but critical, since the treatment and prognosis depend on the disease form and the type of deposited amyloid. Coexistence of clinical conditions such as old age, monoclonal gammopathy, chronic inflammation, or peripheral neuropathy in a patient with cardiomyopathy creates a differential diagnosis between the major types of CA: amyloidosis light chains (AL), amyloidosis transthyretin (ATTR) and amyloidosis A (AA).
OBJECTIVES
To demonstrate the utility of the Western blotting (WB)-based amyloid typing method in patients diagnosed with cardiac amyloidosis where the type of amyloid was not obvious based on the clinical context.
METHODS
Congo red positive endomyocardial biopsy specimens were studied in patients where the type of amyloid was uncertain. Amyloid proteins were extracted and identified by WB. Mass spectrometry (MS) of the electrophoretically resolved protein-in-gel bands was used for confirmation of WB data.
RESULTS
WB analysis allowed differentiation between AL, AA, and ATTR in cardiac biopsies based on specific immunoreactivity of the electrophoretically separated proteins and their characteristic molecular weight. The obtained results were confirmed by MS.
CONCLUSIONS
WB-based amyloid typing method is cheaper and more readily available than the complex and expensive gold standard techniques such as MS analysis or immunoelectron microscopy. Notably, it is more sensitive and specific than the commonly used immunohistochemical techniques and may provide an accessible diagnostic service to patients with amyloidosis in Israel.
Topics: Humans; Amyloidosis; Amyloid; Amyloidogenic Proteins; Cardiomyopathies; Blotting, Western; Amyloid Neuropathies, Familial; Prealbumin
PubMed: 38493325
DOI: No ID Found -
Journal of the American Society of... 2024Fine-needle aspiration (FNA) of abdominal fibroadipose tissue is a commonly utilized method for the detection of amyloidosis. While generally regarded as an accurate and...
INTRODUCTION
Fine-needle aspiration (FNA) of abdominal fibroadipose tissue is a commonly utilized method for the detection of amyloidosis. While generally regarded as an accurate and specific detection method, the sensitivity is variable. The objective of this study was to investigate the performance of fat pad FNAs in detecting amyloidosis relative to other tissue biopsies.
MATERIALS AND METHODS
Fat pad FNA results from January 1, 2014, to December 31, 2022, were catalogued. Clinical data including FNA indication were ascertained for each case. The results of any subsequent tissue biopsy/biopsies evaluated for amyloidosis by Congo red staining were also assessed. Challenges to diagnostic interpretation were explored.
RESULTS
A total of 334 fat pad FNAs were identified. The most common indications were peripheral neuropathy (29.3%), cardiomyopathy/heart failure (28.1%), monoclonal gammopathy (27.8%), and multiple myeloma/lymphoplasmacytic lymphoma (21.0%). Cytologic interpretations were: 7 (2.1%) nondiagnostic, 284 (85.0%) negative, 18 (5.4%) indeterminate, 16 (4.8%) suspicious, and 9 (2.7%) positive for amyloid deposition. In our sample, 103 (30.8%) patients had Congo red testing performed on a subsequent surgical specimen(s) including: 3 of 7 of nondiagnostic cases, none which were positive on the subsequent surgical; 70 of 284 negative cases, 27 which were positive on the subsequent surgical; 11 of 18 indeterminate cases, 7 which were positive on the subsequent surgical; 13 of 16 suspicious cases, 2 which were positive on the subsequent surgical; and 6 of 9 positive cases, 3 which were positive on the subsequent surgical. Challenges to FNA interpretation included scant cellularity, focal staining/birefringence, and overstaining.
CONCLUSIONS
It is best to view fat pad aspiration versus other tissue biopsy results as complimentary diagnostic tests that should be interpreted in the context of the clinical setting and overall clinical suspicion for amyloidosis.
Topics: Humans; Biopsy, Fine-Needle; Male; Female; Middle Aged; Amyloidosis; Aged; Abdominal Fat; Adult; Aged, 80 and over; Retrospective Studies; Sensitivity and Specificity
PubMed: 38493005
DOI: 10.1016/j.jasc.2024.01.003