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European Journal of Heart Failure Apr 2024Despite their potential, sodium-glucose cotransporter 2 inhibitors (SGLT2i) have not been well-studied in transthyretin amyloid cardiomyopathy (ATTR-CM) as randomized...
AIMS
Despite their potential, sodium-glucose cotransporter 2 inhibitors (SGLT2i) have not been well-studied in transthyretin amyloid cardiomyopathy (ATTR-CM) as randomized trials have excluded patients with this morbid disease. We performed a retrospective study assessing the short-term efficacy and safety of SGLT2i in ATTR-CM.
METHODS AND RESULTS
We screened consecutive patients seen at a tertiary care centre and identified 87 ATTR-CM patients treated with SGLT2i and 95 untreated control patients. Endpoints included changes in weight, loop diuretic dose, and cardiac/renal biomarkers. The median age of the overall population was 79 (interquartile range [IQR] 11) years. Nearly 90% of patients were male, and 93% were on a transthyretin stabilizer. Control patients demonstrated generally less severe disease at baseline compared to SGLT2i-treated patients, with lower median Columbia risk score (p < 0.001). Median follow-up time was 5.6 (IQR 5.2) and 8.4 (IQR 2.1) months in the SGLT2i and control cohorts, respectively. Compared with controls, SGLT2i treatment was associated with significantly greater reductions from baseline in weight, loop diuretic dose, and uric acid during follow-up (p < 0.001). While no significant between-group differences were observed on cardiac biomarkers, estimated glomerular filtration rate was significantly reduced versus controls 1 month after SGLT2i initiation (p = 0.002), but no significant differences were observed at later timepoints. Results were similar in a propensity score-matched analysis (n = 42 per cohort). A total of 10 (11.5%) patients discontinued SGLT2i, most commonly due to genitourinary symptoms.
CONCLUSION
Sodium-glucose cotransporter 2 inhibitors were well tolerated by most patients with ATTR-CM and appeared to improve volume status and combat diuretic resistance. Randomized studies are needed to confirm these findings.
Topics: Humans; Male; Female; Sodium-Glucose Transporter 2 Inhibitors; Aged; Retrospective Studies; Treatment Outcome; Amyloid Neuropathies, Familial; Cardiomyopathies; Aged, 80 and over
PubMed: 38488292
DOI: 10.1002/ejhf.3198 -
Scientific Reports Mar 2024Increasing evidence suggests that gut microbiota alterations are related to development and phenotypes of many neuropsychiatric diseases. Here, we evaluated the fecal...
Increasing evidence suggests that gut microbiota alterations are related to development and phenotypes of many neuropsychiatric diseases. Here, we evaluated the fecal microbiota and its clinical correlates in patients with hereditary transthyretin amyloidosis (ATTRv) and polyneuropathy. Fecal microbiota from 38 ATTRv patients and 39 age-matched controls was analyzed by sequencing 16S V3-V4 ribosomal RNA, and its relationships with clinical characteristics of polyneuropathy and cardiomyopathy were explored. The familial amyloidotic polyneuropathy stage was stage I, II, and III in 13, 18, and 7 patients. Tc-PYP SPECT showed a visual score of 2 in 15 and 3 in 21 patients. The gut microbiota of ATTRv patients showed higher alpha diversity (ASV richness and Shannon effective numbers) and dissimilar beta diversity compared to controls. Relative abundance of microbiota was dominated by Firmicutes and decreased in Bacteroidetes in ATTRv patients than in controls. Patients with more myocardial amyloid deposition were associated with increased alpha diversity, and the abundance of Clostridia was significantly correlated with pathophysiology of polyneuropathy in ATTRv patients. These findings demonstrated alterations in the gut microbiota, especially Firmicutes, in ATTRv. The association between altered microbiota and phenotypes of cardiomyopathy and polyneuropathy might suggest potential contributions of gut microbiota to ATTRv pathogenesis.
Topics: Humans; Amyloid Neuropathies, Familial; Cardiomyopathies; Firmicutes; Gastrointestinal Microbiome; Polyneuropathies; RNA, Ribosomal, 16S
PubMed: 38486098
DOI: 10.1038/s41598-024-56984-5 -
ACS Chemical Neuroscience Apr 2024Transthyretin (TTR) is a tetrameric homologous protein that can dissociate into monomers. Misfolding and aggregation of TTR can lead to amyloid transthyretin amyloidosis...
Transthyretin (TTR) is a tetrameric homologous protein that can dissociate into monomers. Misfolding and aggregation of TTR can lead to amyloid transthyretin amyloidosis (ATTR), which can cause many diseases (e.g., senile systemic amyloidosis, familial amyloid cardiomyopathy, and familial amyloid polyneuropathy). Despite growing evidence indicating that small oligomers play a critical role in regulating cytotoxicity, the structures of these oligomeric intermediates and their conformational transformations are still unclear, impeding our understanding of neurodegenerative mechanisms and the development of therapeutics targeting early aggregation species. The TTR monomer protein consists of various fragments prone to self-aggregation, including the residue 105-115 sequence. Therefore, our study investigated the assembly progress of ATTR (105-115) peptides using all-atom molecular dynamics simulations. The findings indicate that the probability of β-sheet content increases with increasing numbers of peptides. Additionally, interactions between hydrophobic residues L110 and L111 are crucial for the formation of a β-rich oligomer formation. These β-rich oligomers may adopt β-barrel conformations, potentially toxic oligomer species. Free-energy analysis reveals that β-barrel conformations serve as intermediates for these β-rich oligomers. Our insights into the structural ensemble dynamics of ATTR (105-115) contribute to understanding the physical mechanisms underlying the β-barrel oligomers of ATTR. These findings may shed light on the pathological role of ATTR in neurodegenerative diseases and offer potential therapeutic targets.
Topics: Prealbumin; Amyloid; Molecular Dynamics Simulation; Amyloidogenic Proteins; Peptides; Entropy; Amyloid Neuropathies, Familial
PubMed: 38483181
DOI: 10.1021/acschemneuro.3c00574 -
Journal of the American College of... Mar 2024Cardiac amyloidosis is increasingly recognized as a treatable form of heart failure. Highly effective specific therapies have recently become available for the 2 most... (Review)
Review
Cardiac amyloidosis is increasingly recognized as a treatable form of heart failure. Highly effective specific therapies have recently become available for the 2 most frequent forms of cardiac amyloidosis: immunoglobulin light chain amyloidosis and transthyretin (ATTR) amyloidosis. Nevertheless, initiation of specific therapies requires recognition of cardiac amyloidosis and appropriate characterization of the amyloid type. Although noninvasive diagnosis is possible for ATTR cardiac amyloidosis, histological demonstration and typing of amyloid deposits is still required for a substantial number of patients with ATTR and in all patients with light chain amyloidosis and other rarer forms of cardiac amyloidosis. Amyloid histological typing can be performed using different techniques: mass spectrometry, immunohistochemistry, and immunoelectron microscopy. This review describes which patients require histological confirmation of cardiac amyloidosis along with when and how to type amyloid deposits in histologic specimens. Furthermore, it covers the characteristics and limitations of the different typing methods that are available in clinical practice.
Topics: Humans; Plaque, Amyloid; Amyloidosis; Amyloid; Heart Failure; Immunohistochemistry; Amyloidogenic Proteins; Prealbumin; Amyloid Neuropathies, Familial; Cardiomyopathies
PubMed: 38479957
DOI: 10.1016/j.jacc.2024.01.010 -
Amyloid : the International Journal of... Jun 2024To evaluate serum neurofilament light chain (sNfL) as biomarker of disease onset, progression and treatment effect in hereditary transthyretin (ATTRv) amyloidosis...
OBJECTIVE
To evaluate serum neurofilament light chain (sNfL) as biomarker of disease onset, progression and treatment effect in hereditary transthyretin (ATTRv) amyloidosis patients and variant (v) carriers.
METHODS
sNfL levels were assessed longitudinally in persistently asymptomatic v carriers ( = 12), persistently asymptomatic ATTRv amyloidosis patients (defined as asymptomatic patients but with amyloid detectable in subcutaneous abdominal fat tissue) ( = 8), in v carriers who developed polyneuropathy ( = 7) and in ATTRv amyloidosis patients with polyneuropathy on treatment (TTR-stabiliser ( = 20) or TTR-silencer ( = 18)). Polyneuropathy was confirmed by nerve conduction studies or quantitative sensory testing. sNfL was analysed using a single-molecule array assay.
RESULTS
sNfL increased over 2 years in persistently asymptomatic ATTRv amyloidosis patients, but did not change in persistently asymptomatic v carriers. In all v carriers who developed polyneuropathy, sNfL increased from 8.4 to 49.8 pg/mL before the onset of symptoms and before polyneuropathy could be confirmed neurophysiologically. In symptomatic ATTRv amyloidosis patients on a TTR-stabiliser, sNfL remained stable over 2 years. In patients on a TTR-silencer, sNfL decreased after 1 year of treatment.
CONCLUSION
sNfL is a biomarker of early neuronal damage in ATTRv amyloidosis already before the onset of polyneuropathy. Current data support the use of sNfL in screening asymptomatic v carriers and in monitoring of disease progression and treatment effect.
Topics: Humans; Amyloid Neuropathies, Familial; Neurofilament Proteins; Male; Female; Middle Aged; Biomarkers; Aged; Prealbumin; Longitudinal Studies; Adult; Polyneuropathies; Neurons
PubMed: 38477065
DOI: 10.1080/13506129.2024.2327342 -
Cureus Feb 2024Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant hereditary disorder. In Portugal, it is mainly linked to transthyretin (TTR) mutation, and patients...
Familial amyloidotic polyneuropathy (FAP) is an autosomal dominant hereditary disorder. In Portugal, it is mainly linked to transthyretin (TTR) mutation, and patients present with length-dependent sensory-motor polyneuropathy, often accompanied by autonomic dysfunction. Treatment options for FAP include liver transplant, and due to the lack of organs, FAP livers began being implanted in patients with severe liver disease in a process known as domino liver transplantation (DLT). We report a case of a 68-year-old Portuguese man, with post-hepatitis C-related cirrhosis liver transplantation, who presented to his family doctor with decreased sensitivity in both feet and weight loss, which were initially attributed to diabetic neuropathy and an adjustment in diabetic medication, respectively. Symptoms evolved to changes in both feet's thermal and painful sensitivity, reduced sensitivity in both hands, diarrhea, and progressive weight loss. At this time, the patient's disclosure of receiving a DLT prompted the correct diagnosis of iatrogenic amyloid polyneuropathy. This case underscores the challenges in diagnosing and managing iatrogenic amyloid polyneuropathy following DLT, highlighting the importance of prompt identification of DLT recipients, active vigilance of these patients via structured monitoring, and increased healthcare providers' awareness of this practice so that early signs of the disease may be recognized.
PubMed: 38449948
DOI: 10.7759/cureus.53605 -
JAMA Cardiology Apr 2024Cardiopulmonary exercise testing (CPET) has an established role in the assessment of patients with heart failure. However, data are lacking in patients with...
IMPORTANCE
Cardiopulmonary exercise testing (CPET) has an established role in the assessment of patients with heart failure. However, data are lacking in patients with transthyretin (ATTR) amyloidosis.
OBJECTIVE
To use CPET to characterize the spectrum of functional phenotypes in patients with ATTR amyloidosis and assess their association with the cardiac amyloid burden as well as the association between CPET parameters and prognosis.
DESIGN, SETTING AND PARTICIPANTS
This single-center study evaluated patients diagnosed with ATTR amyloidosis from May 2019 to September 2022 who underwent CPET at the National Amyloidosis Centre. Of 1045 patients approached, 506 were included and completed the study. Patients were excluded if they had an absolute contraindication to CPET or declined participation. The mean (SD) follow-up period was 22.4 (11.6) months.
MAIN OUTCOMES AND MEASURES
Comparison of CPET parameters across disease phenotypes (ATTR with cardiomyopathy [ATTR-CM], polyneuropathy, or both [ATTR-mixed]), differences in CPET parameters based on degree of amyloid infiltration (as measured by cardiovascular magnetic resonance [CMR] with extracellular volume mapping), and association between CPET parameters and prognosis.
RESULTS
Among the 506 patients with ATTR amyloidosis included in this study, the mean (SD) age was 73.5 (10.2) years, and 457 participants (90.3%) were male. Impairment in functional capacity was highly prevalent. Functional impairment in ATTR-CM and ATTR-mixed phenotypes (peak mean [SD] oxygen consumption [VO2], 14.5 [4.3] mL/kg/min and 15.7 [6.2] mL/kg/min, respectively) was observed alongside impairment in the oxygen pulse, with ventilatory efficiency highest in ATTR-CM (mean [SD] ventilatory efficiency/volume of carbon dioxide expired slope, 38.1 [8.6]). Chronotropic incompetence and exercise oscillatory ventilation (EOV) were highly prevalent across all phenotypes, with both the prevalence and severity being higher than in heart failure from different etiologies. Worsening of amyloid burden on CMR was associated with decline in multiple CPET parameters, although chronotropic response and EOV remained abnormal irrespective of amyloid burden. On multivariable Cox regression analysis, peak VO2 and peak systolic blood pressure (SBP) were independently associated with prognosis (peak VO2: hazard ratio, 0.89 [95% CI, 0.81-0.99; P = .03]; peak SBP: hazard ratio, 0.98 [95% CI, 0.97-0.99; P < .001]).
CONCLUSIONS AND RELEVANCE
In this study, ATTR amyloidosis was characterized by distinct patterns of functional impairment between all disease phenotypes. A high prevalence of chronotropic incompetence, EOV, and ventilatory inefficiency were characteristic of this population. CPET parameters were associated with amyloid burden by CMR and with peak VO2, and SBP, which have been shown to be independent predictors of mortality. These findings suggest that CPET may be useful in characterizing distinct patterns of functional impairment across the spectrum of amyloid infiltration and predicting outcomes, and potentially offers a more comprehensive method of evaluating functional capacity for future prospective studies.
Topics: Humans; Male; Aged; Female; Exercise Test; Prospective Studies; Amyloid Neuropathies, Familial; Cardiomyopathies; Heart Failure
PubMed: 38446436
DOI: 10.1001/jamacardio.2024.0022 -
Amyloid : the International Journal of... Jun 2024Hereditary transthyretin cardiac amyloidosis (ATTRv-CA) has a long latency phase before clinical onset, creating a need to identify subclinical disease. We hypothesized...
BACKGROUND
Hereditary transthyretin cardiac amyloidosis (ATTRv-CA) has a long latency phase before clinical onset, creating a need to identify subclinical disease. We hypothesized circulating transthyretin (TTR) and retinol binding protein 4 (RBP4) levels would be associated with carrier status and correlated with possible evidence of subclinical ATTRv-CA.
METHODS
TTR and RBP4 were measured in blood samples from V122I carriers and age-, sex- and race-matched non-carrier controls (1:2 matching) among Dallas Heart Study participants (phases 1 (DHS-1) and 2 (DHS-2)). Multivariable linear regression models determined factors associated with TTR and RBP4.
RESULTS
There were 40 V122I carriers in DHS-1 and 54 V122I carriers in DHS-2. In DHS-1 and DHS-2, TTR was lower in V122I carriers ( < .001 for both), and RBP4 in DHS-2 was lower in V122I carriers than non-carriers ( = .002). Among V122I carriers, TTR was negatively correlated with markers of kidney function, and limb lead voltage ( < .05 for both) and TTR and RBP4 were correlated with atrial volume in DHS-2 ( < .05).
CONCLUSIONS
V122I TTR carrier status is independently associated with lower TTR and RBP4 in comparison with non-carriers. These findings support the hypothesis that TTR and RBP4 may correlate with evidence of subclinical ATTRv-CA.
Topics: Humans; Prealbumin; Retinol-Binding Proteins, Plasma; Male; Female; Middle Aged; Amyloid Neuropathies, Familial; Heterozygote; Adult; Aged
PubMed: 38445629
DOI: 10.1080/13506129.2024.2322479 -
European Journal of Heart Failure Mar 2024To evaluate the effect of long-term tafamidis treatment on health-related quality of life (HRQoL) in patients with transthyretin amyloid cardiomyopathy (ATTR-CM)... (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS
To evaluate the effect of long-term tafamidis treatment on health-related quality of life (HRQoL) in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) enrolled in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) and long-term extension (LTE) study.
METHODS AND RESULTS
We examined change from baseline in Kansas City Cardiomyopathy Questionnaire overall summary (KCCQ-OS) and clinical summary (KCCQ-CS) scores in patients who received tafamidis meglumine 80 mg for 30 months in ATTR-ACT and tafamidis (meglumine 80 mg or bioequivalent free acid 61 mg) for 30 months in the LTE study, and in patients who received placebo for 30 months in ATTR-ACT and tafamidis for 30 months in the LTE study. In ATTR-ACT, 176 and 177 patients were randomized to tafamidis 80 mg and placebo, respectively. Patients who continuously received tafamidis had a 6- to 7-point reduction in least squares (LS) mean (standard error) KCCQ-OS and KCCQ-CS scores at month 30 (-6.25 [1.53] and -7.48 [1.39]), with little or no further decline over the next 30 months (-5.92 [1.77] and -9.21 [1.88] at month 60). Patients who received placebo in ATTR-ACT had a 20-point reduction in LS mean KCCQ-OS and KCCQ-CS scores at month 30 (-19.60 [1.94] and -19.90 [2.01]), but the decline slowed after initiating tafamidis (-24.70 [3.04] and -25.30 [3.36] at month 60).
CONCLUSION
Tafamidis reduced HRQoL decline in patients with ATTR-CM. Patients continuously treated with tafamidis for 60 months demonstrated stabilized HRQoL. In patients who initially received placebo in ATTR-ACT, tafamidis reduced the decline in HRQoL during the LTE study.
Topics: Humans; Quality of Life; Male; Female; Benzoxazoles; Amyloid Neuropathies, Familial; Aged; Cardiomyopathies; Middle Aged; Double-Blind Method; Treatment Outcome; Surveys and Questionnaires; Time Factors
PubMed: 38439606
DOI: 10.1002/ejhf.3190 -
European Journal of Heart Failure Mar 2024
Prevalence of wild-type transthyretin amyloidosis in a prospective heart failure cohort with preserved and mildly reduced ejection fraction: Results of the Amylo-VIP-HF study.
Topics: Humans; Heart Failure; Amyloid Neuropathies, Familial; Stroke Volume; Male; Female; Prevalence; Prospective Studies; Aged; Middle Aged; Prealbumin
PubMed: 38439596
DOI: 10.1002/ejhf.3186