Assessment of transthyretin instability in patients with wild-type transthyretin amyloid cardiomyopathy.
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SUBMITTER: Iino T
PROVIDER: S-EPMC11371834 | biostudies-literature | 2024 Sep
REPOSITORIES: biostudies-literature
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Assessment of transthyretin instability in patients with wild-type transthyretin amyloid cardiomyopathy.
Iino Takuya T Nagao Manabu M Tanaka Hidekazu H Yoshikawa Sachiko S Asakura Junko J Nishimori Makoto M Shinohara Masakazu M Harada Amane A Watanabe Shunsuke S Ishida Tatsuro T Hirata Ken-Ichi KI Toh Ryuji R
Scientific reports 20240903 1
The pathophysiology of variant transthyretin (TTR) amyloidosis (ATTRv) is associated with destabilizing mutations in the TTR tetramer. However, why TTR with a wild-type genetic sequence misfolds and aggregates in wild-type transthyretin amyloidosis (ATTRwt) is unknown. Here, we evaluate kinetic TTR stability with a newly developed ELISA system in combination with urea-induced protein denaturation. Compared with that in control patients, endogenous TTR in patients with wild-type transthyretin amy ...[more]
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Project description:BackgroundLeft ventricular (LV) apical sparing by transthoracic echocardiography (TTE) has not been widely accepted to diagnose transthyretin amyloid cardiomyopathy (ATTR-CM), because it is time consuming and requires a level of expertise. We hypothesized that automatic assessment may be the solution for these problems.Methods-and-resultsWe enrolled 63 patients aged ≥70 years who underwent 99mTc-labeled pyrophosphate (99mTc-PYP) scintigraphy on suspicion of ATTR-CM and performed TTE by EPIQ7G, and had enough information for two-dimensional speckle tracking echocardiography at Kumamoto University Hospital from January 2016 to December 2019. LV apical sparing was described as a high relative apical longitudinal strain (LS) index (RapLSI). Measurement of LS was repeated using the same apical images with three different measurement packages as follows: (1) full-automatic assessment, (2) semi-automatic assessment, and (3) manual assessment. The calculation time for full-automatic assessment (14.7 ± 1.4 sec/patient) and semi-automatic assessment (66.7 ± 14.4 sec/patient) were significantly shorter than that for manual assessment (171.2 ± 59.7 sec/patient) (p < 0.01 for both). Receiver operating characteristic curve analysis showed that the area under curve of the RapLSI evaluated by full-automatic assessment for predicting ATTR-CM was 0.70 (best cut-off point; 1.14 [sensitivity 63%, specificity 81%]), by semi-automatic assessment was 0.85 (best cut-off point; 1.00 [sensitivity, 66%; specificity, 100%]) and by manual assessment was 0.83 (best cut-off point; 0.97 [sensitivity, 72%; specificity, 97%]).ConclusionThere was no significant difference between the diagnostic accuracy of RapLSI estimated by semi-automatic assessment and that estimated by manual assessment. Semi-automatically assessed RapLSI is useful to diagnose ATTR-CM in terms of rapidity and diagnostic accuracy.
| S-EPMC10320495 | biostudies-literature
Project description:BackgroundTransthyretin amyloid cardiomyopathy results from the accumulation of wild-type (ATTRwt) or variant (ATTRv) transthyretin amyloid fibrils in the myocardium. THAOS (Transthyretin Amyloidosis Outcomes Survey) is a global, longitudinal, observational survey of patients with ATTRv and ATTRwt amyloidosis and asymptomatic patients with transthyretin mutations.ObjectivesThis study explored temporal trends in ATTRwt amyloidosis diagnoses using data from THAOS.MethodsUsing THAOS data from December 2007 to January 2020, the following comparisons were made according to year: ATTRwt amyloidosis diagnoses in the United States versus rest of the world, ATTRwt versus ATTRv amyloidosis with cardiac-associated mutations diagnoses, and ATTRwt amyloidosis diagnoses by tissue biopsy versus bone scintigraphy.ResultsThere were 1,069 patients with ATTRwt amyloidosis and 525 with ATTRv amyloidosis with cardiac mutations enrolled in THAOS. The median time from symptom onset to ATTRwt amyloidosis diagnosis did not change over the past 5 years (>60 months from 2015-2019). ATTRwt amyloidosis diagnoses increased from 2 in 2005 to >100 per year from 2016, with a more pronounced increase in the United States compared with the rest of the world. Diagnoses of ATTRwt amyloidosis by tissue biopsy increased yearly and peaked in 2014 before declining, whereas diagnoses by bone scintigraphy increased markedly since 2011. ATTRv amyloidosis with cardiac mutation diagnoses increased from 3 in 2005 to 37 in 2011, then plateaued. The proportion of patients with ATTRwt amyloidosis diagnosed with New York Heart Association functional class III/IV heart failure decreased from 2012 (46.4%) to 2019 (16.0%).ConclusionsIn the past decade, ATTRwt amyloidosis diagnoses increased worldwide. Despite the growing utilization of bone scintigraphy, patients are diagnosed several years after symptom onset. (Transthyretin Amyloidosis Outcomes Survey [THAOS]; NCT00628745).
| S-EPMC8543133 | biostudies-literature
Project description:AimsThis study was performed to investigate whether left atrial (LA) strain by echocardiography provides prognostic information in patients with wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM).Methods and resultsAmong 129 patients who were diagnosed with ATTRwt-CM at Kumamoto University Hospital from December 2002 to December 2019, 113 patients who had enough information for two-dimensional speckle tracking echocardiography were enrolled in this study. During a median follow-up of 668 days, 28 cardiovascular deaths occurred. Compared with patients in the non-event group, those in the cardiovascular death group were significantly older (81.5 ± 7.4 vs. 78.1 ± 6.1 years, P < 0.01), had a lower incidence of carpal tunnel syndrome (21% vs. 47%, P < 0.05), and had a higher high-sensitivity cardiac troponin T [0.085 (0.063-0.105) vs. 0.049 (0.036-0.079) ng/mL, P < 0.01] and B-type natriuretic peptide concentrations [419 (239-541) vs. 271 (155-462) pg/mL, P < 0.01] and lower estimated glomerular filtration rate (41.8 ± 15.4 vs. 53.4 ± 14.6 mL/min/1.73 m2 , P < 0.01). Electrocardiography showed higher rate of a V1-V3 QS pattern (52% vs. 24%, P < 0.01) and complete left bundle branch block (27% vs. 6%, P < 0.01), and echocardiography showed a significantly lower peak LA strain rate during the contraction phase (0.16 ± 0.13 vs. 0.28 ± 0.27 S-1 , P < 0.05), LA strain during the reservoir phase (LASr) (5.84 ± 2.41 vs. 8.22 ± 4.05%, P < 0.01), and peak LA strain rate during the reservoir phase (0.26 ± 0.09 vs. 0.33 ± 0.15 S-1 , P < 0.05) in the cardiovascular death group than in non-event group. By contrast, conventional echocardiographic findings were not significantly different between these two groups. After adjusting for conventional predictive factors of ATTRwt-CM (age, high-sensitivity cardiac troponin T and B-type natriuretic peptide concentrations, and estimated glomerular filtration rate), multivariable Cox proportional hazard analyses showed that LASr was significantly and independently associated with cardiovascular death in patients with ATTRwt-CM (odds ratio, 0.84; 95% confidence interval, 0.72-0.98; P < 0.05). After adjusting for age and echocardiographic findings associated with cardiovascular death (LA volume index and peak LA strain rate during the contraction phase), LASr was significantly and independently associated with cardiovascular death in patients with ATTRwt-CM (odds ratio, 0.83; 95% confidence interval, 0.70-0.98; P < 0.05). Receiver operating characteristic curve analysis showed that the area under the curve of LASr for cardiovascular death was 0.686 and that the best cut-off value of LASr was 6.69% (sensitivity, 62.4%; specificity, 64.3%). In the Kaplan-Meier analysis, patients with low LASr (<6.69%) had a significantly higher probability of total cardiovascular death (P < 0.05) and heart failure-related hospitalization (P < 0.05).ConclusionsLeft atrial strain during the reservoir phase provides significant prognostic value in patients with ATTRwt-CM even after adjusting for conventional predictive factors.
| S-EPMC8712780 | biostudies-literature
Project description:Wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) is an underrecognized cause of heart failure due to misfolded wild-type transthyretin (TTRwt) myocardial deposition. The development of wild-type TTR amyloid fibrils is a complex pathological process linked to the deterioration of homeostatic mechanisms owing to aging, plausibly implicating multiple molecular mechanisms. The components of amyloid transthyretin often include serum amyloid P, proteoglycans, and clusterin, which may play essential roles in the localization and elimination of amyloid fibrils. Oxidative stress, impaired mitochondrial function, and perturbation of intracellular calcium dynamics induced by TTR contribute to cardiac impairment. Recently, tafamidis has been the only drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of ATTRwt-CM. In addition, small interfering RNAs and antisense oligonucleotides for ATTR-CM are promising therapeutic approaches and are currently in phase III clinical trials. Newly emerging therapies, such as antibodies targeting amyloid, inhibitors of seed formation, and CRISPR‒Cas9 technology, are currently in the early stages of research. The development of novel therapies is based on progress in comprehending the molecular events behind amyloid cardiomyopathy. There is still a need to further advance innovative treatments, providing patients with access to alternative and effective therapies, especially for patients diagnosed at a late stage.
| S-EPMC10942909 | biostudies-literature
Project description:BackgroundGeneral interest and incidence are increasing in wild-type transthyretin amyloidosis (ATTRwt) in recent time. As patient population increases, further knowledge of the management of the frequently encountered interacting cardiac comorbidities is requested to improve treatment of ATTRwt patients.Case summaryA 73-year-old male ATTRwt patient presented to the outpatient clinic (Day 0) with dyspnoea, leg swelling, and palpitations. At diagnosis, 3 years prior to presentation, he exhibited only minor signs of ATTRwt. At Day 0, clinical examination revealed atrial fibrillation and mild peripheral oedema. Anticoagulant and symptomatic treatment with beta-blocker and diuretics was initiated, and the patient was planned for sub-acute direct cardioversion, and the patient was discharged with a Holter monitor to outpatient care. At Day 7, analysis of the monitoring demonstrated spontaneous conversion to sinus rhythm and, unexpectedly, episodes of high-rate self-remittent sustained monomorphic ventricular tachycardia (VT) and frequent ventricular ectopic beats. At Day 8, a sub-acute coronary angiography was performed which revealed a significant proximal left anterior descending artery stenosis which was treated with percutaneous coronary intervention (PCI) and subsequently an internal defibrillator was implanted. Following visits at 1- and 3-month post-PCI at the outpatient clinic revealed no VT and suppression of ventricular ectopic beats.DiscussionThe case illustrates some of the frequently encountered cardiac comorbidities (e.g. atrial fibrillation, ventricular arrhythmia, and ischaemic heart disease) associated with ATTRwt. A high level of suspicion is warranted to identify treatable cardiac conditions [atrial fibrillation, atrioventricular (AV) block, and ischaemic heart disease] and to uncover potentially fatal cardiac conditions in patients with ATTRwt.
| S-EPMC10493642 | biostudies-literature
Project description:Transthyretin amyloid cardiomyopathy, an often unrecognized cause of heart failure, is now treatable with a transthyretin stabilizer. It is therefore important to identify at-risk patients who can undergo targeted testing for earlier diagnosis and treatment, prior to the development of irreversible heart failure. Here we show that a random forest machine learning model can identify potential wild-type transthyretin amyloid cardiomyopathy using medical claims data. We derive a machine learning model in 1071 cases and 1071 non-amyloid heart failure controls and validate the model in three nationally representative cohorts (9412 cases, 9412 matched controls), and a large, single-center electronic health record-based cohort (261 cases, 39393 controls). We show that the machine learning model performs well in identifying patients with cardiac amyloidosis in the derivation cohort and all four validation cohorts, thereby providing a systematic framework to increase the suspicion of transthyretin cardiac amyloidosis in patients with heart failure.
| S-EPMC8113237 | biostudies-literature
Project description:AimsThe focus on wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) is increasing because of novel treatment options. There is currently no report on a large number of Japanese patients with ATTRwt-CM. The study aimed to examine the characteristics and prognosis of ATTRwt-CM in Japan.Methods and resultsConsecutive patients (78.5 ± 6.4 years old at diagnosis) with ATTRwt-CM diagnosed at Kumamoto University Hospital between December 2002 and December 2019 were retrospectively reviewed. Data, including demographic characteristics, co-morbidities, clinical manifestations at diagnosis, laboratory results, electrocardiographic and echocardiographic data, imaging and pathological findings, and treatment were obtained. Of 129 patients included in this study, 110 patients (85%) were male. The median period from initial symptom onset to diagnosis was 15.5 (2-75) months. Heart failure was the most common clinical manifestation leading to diagnosis (61%) and initial manifestations (49%). Of 106 patients, carpal tunnel syndrome was observed in 57 patients (54%), and the median period from initial symptom onset to diagnosis was 96 (48-120) months. Histopathological confirmation of transthyretin amyloid was achieved in 94 patients (73%), including 66 (51%) and 28 cases (22%) with endomyocardial and extracardiac biopsies. During the observation period (median 15.0 [inter-quartile range, 5.4-33.2] months after diagnosis), 34 patients (26%) died. Of these, 27 patients (79%) had cardiovascular deaths (heart failure, 25; sudden death, two). The median survival duration was 58.9 months and the 5 years' survival rate was 48%. According to a multivariate Cox hazard analysis, age [hazard ratio (HR), 1.14; 95% confidence interval (CI), 1.05-1.23, P = 0.002] and low serum sodium levels (HR, 0.89; 95% CI, 0.79-0.996; P = 0.04) contributed to all-cause mortality, and low serum sodium levels contributed to hospitalization for heart failure (HR, 0.86; 95% CI, 0.77-0.96; P = 0.005).ConclusionsClinical characteristics and prognosis of ATTRwt-CM patients in Japan were examined. Carpal tunnel syndrome can be considered an indication for diagnosis of ATTRwt-CM. Age and low serum sodium level were significant predictive factors of all survival outcomes. The clinical features of ATTRwt-CM should be recognized to provide appropriate treatment.
| S-EPMC7524255 | biostudies-literature
Project description:AimThis study was conducted to investigate the meaning of left ventricular (LV) apical sparing in patients with wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM).Methods and results165 patients who were diagnosed with ATTRwt-CM at Kumamoto University Hospital from January 2002 to December 2020 and had sufficient data for two-dimensional speckle tracking echocardiography were enrolled. Of these, 86 patients (52 %) had LV apical sparing (relative apical longitudinal strain index (RapLSI) > 1.0). Multivariable logistic regression analysis revealed the following variables were significantly associated with LV apical sparing: interventricular septal thickness in diastole (odds ratio (OR), 1.19; 95 % confidence interval (CI), 1.01-1.41; p < 0.05); E/e' ratio (OR, 1.06; 95 % CI, 1.00-1.11; p < 0.05); and heart-to-contralateral ratio by 99mTc-labeled pyrophosphate scintigraphy (OR, 3.40; 95 % CI, 1.07-10.83; p < 0.05).Next, we compared RapLSI at the time of diagnosis with that during the follow-up period (396 days (346-458) after diagnosis) in 92 patients. RapLSI increased significantly during the follow-up period compared with RapLSI at diagnosis in the non-LV apical sparing group (0.89 ± 0.32 vs 0.74 ± 0.18, p < 0.01) but not in the LV apical sparing group (1.33 ± 0.53 vs 1.39 ± 0.45, p = 0.46). A total of 12 patients (29 %) in the non-LV apical sparing group developed LV apical sparing and 11 patients (22 %) in LV apical sparing group diminished LV apical sparing during the follow-up period.ConclusionApproximately half of ATTRwt-CM patients did not have LV apical sparing at diagnosis. Because RapLSI in ATTRwt-CM significantly changed over time, repeated two-dimensional speckle tracking analysis is important for suspected ATTR-CM patients.
| S-EPMC9643881 | biostudies-literature
Project description:Wild-type transthyretin amyloid cardiomyopathy (ATTRwt CM) is a more common disease than previously thought. Awareness of ATTRwt CM and its diagnosis has been challenged by its unspecific and widely distributed clinical manifestations and traditionally invasive diagnostic tools. Recent advances in echocardiography and cardiac magnetic resonance (CMR), non-invasive diagnosis by bone scintigraphy, and the development of disease-modifying treatments have resulted in an increased interest, reflected in multiple publications especially during the last decade. To get an overview of the scientific knowledge and gaps related to patient entry, suspicion, diagnosis, and systematic screening of ATTRwt CM, we developed a framework to systematically map the available evidence of (i) when to suspect ATTRwt CM in a patient, (ii) how to diagnose the disease, and (iii) which at-risk populations to screen for ATTRwt CM. Articles published between 2010 and August 2021 containing part of or a full diagnostic pathway for ATTRwt CM were included. From these articles, data for patient entry, suspicion, diagnosis, and screening were extracted, as were key study design and results from the original studies referred to. A total of 50 articles met the inclusion criteria. Of these, five were position statements from academic societies, while one was a clinical guideline. Three articles discussed the importance of primary care providers in terms of patient entry, while the remaining articles had the cardiovascular setting as point of departure. The most frequently mentioned suspicion criteria were ventricular wall thickening (44/50), carpal tunnel syndrome (42/50), and late gadolinium enhancement on CMR (43/50). Diagnostic pathways varied slightly, but most included bone scintigraphy, exclusion of light-chain amyloidosis, and the possibility of doing a biopsy. Systematic screening was mentioned in 16 articles, 10 of which suggested specific at-risk populations for screening. The European Society of Cardiology recommends to screen patients with a wall thickness ≥12 mm and heart failure, aortic stenosis, or red flag symptoms, especially if they are >65 years. The underlying evidence was generally good for diagnosis, while significant gaps were identified for the relevance and mutual ranking of the different suspicion criteria and for systematic screening. Conclusively, patient entry was neglected in the reviewed literature. While multiple red flags were described, high-quality prospective studies designed to evaluate their suitability as suspicion criteria were lacking. An upcoming task lies in defining and evaluating at-risk populations for screening. All are steps needed to promote early detection and diagnosis of ATTRwt CM, a prerequisite for timely treatment.
| S-EPMC9065854 | biostudies-literature
Project description:IntroductionThis study investigates the gender distribution in patients diagnosed with wild-type transthyretin amyloidosis cardiomyopathy (ATTRwt).MethodsA systematic review and meta-analysis of the male proportion in diagnosed ATTRwt patients were conducted. To avoid overlapping population, pooled estimates in the primary analysis were based on all unique studies. In secondary analyses, we considered predefined subsets of studies based on study sample size, recruitment years, geography, study design, age at diagnosis, and method of diagnosis. Additional meta-regression analyses were tested for potential determinants of gender distribution.ResultsTwenty-eight unique studies (2542 patients) were included in the meta-analysis. Male proportion in patients with ATTRwt was 86.9% (95% confidence interval 81.5-91.6%). Studies, including patients older than 80 years at diagnosis, had a 29.1% (p value < 0.001) lower male proportion compared to studies, including younger patients. After adjusting for age, studies using autopsy as a method of diagnosis had a 21.1% (p value 0.002) lower male proportion compared to other studies.ConclusionsStudies conducted to date suggest ATTRwt disproportionally affects males. The proportion of males was significantly impacted by the age at diagnosis and method diagnosis, which may suggest important gender-based differences in the clinical manifestation and diagnostic challenges of ATTRwt in females that warrant future research.
| S-EPMC8126539 | biostudies-literature