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Frailty in Wild-Type Transthyretin Cardiac Amyloidosis: The Tip of the Iceberg.

ABSTRACT: ATTRwt-CA occurs in elderly patients and leads to severe heart failure. The disease mechanism involves cardiac and extracardiac infiltration by amyloid fibrils. The objectives of this study are to describe the frailty phenotype in patients with ATTRwt-CA and to assess the associations between frailty parameters, the severity of cardiac involvement, and the course of amyloid disease. We used multidimensional geriatric tools to prospectively assess frailty in patients with ATTRwt-CA consulting (in 2018-2019) in the French National Reference Center for Cardiac Amyloidosis. We included 36 patients (35 males; median age: 82 years (76-86). A third of the patients were categorized as NYHA class III or IV, and 39% had an LVEF below 45%. The median serum NTproBNP was 3188 (1341-8883) pg/mL. The median duration of amyloidosis was 146 months (73-216). The frequency of frailty was 50% and 33% according to the physical frailty phenotype and the Short Emergency Geriatric Assessment questionnaire, respectively. Frailty affected a large number of domains, namely autonomy (69%), balance (58%), muscle weakness (74%), malnutrition (39%), dysexecutive syndrome (72%), and depression (49%). The severity of CA was significantly associated with many frailty parameters independently of age. Balance disorders and poor mobility were also significantly associated with a longer course of amyloid disease. Frailty is frequent in patients with ATTRwt-CA. Some frailty parameters were significantly associated with a longer course of amyloid disease and CA severity. Taking into account frailty in the assessment and management of ATTRwt should improve patients' quality of life.

SUBMITTER: Broussier A

PROVIDER: S-EPMC8348590 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Negative bone scintigraphy in wild-type transthyretin cardiac amyloidosis.

Project description:BACKGROUND:Amyloidosis is a rare systemic disease due to the extracellular tissue deposition of a fibrillar-shaped misfolded protein, called amyloid. Only two types of proteins commonly affect the heart leading to an infiltrative cardiomyopathy: immunoglobulin light chain and transthyretin (TTR) cardiac amyloidosis (CA). Despite the promising role of emerging imaging modalities, such as strain echocardiography, cardiac magnetic resonance and bone scintigraphy, its diagnosis is still often missed or delayed due to their inherent limitations and to a nonspecific clinical scenario with frequent concomitance of cardiac comorbidities. The gold standard for a definite diagnosis still remains endomyocardial biopsy, but in rare cases Congo Red staining could provide false negative results, as in our case, requiring immunoelectron microscopy. CASE PRESENTATION:A middle-aged male adult presented to the emergency department for relapse of heart failure. Echocardiography and cardiac magnetic resonance, along with the history of bilateral carpal tunnel syndrome, were suspicious for TTR-CA. The diagnosis, however, was hampered by concomitant cardiac comorbidities and conflicting results of imaging modalities. In fact bone scintigraphy was negative, as well as Congo Red Staining on myocardial tissue samples obtained by endomyocardial biopsy. Given the high clinical suspicion, immunoelectron microscopy was performed, showing TTR amyloid fibrils deposits, that confirmed the diagnosis. A genetic analysis excluded and hereditary form. The patient was then referred to a specialist center for specific treatment. CONCLUSIONS:This is a rare case of a TTR-CA with a negative Bone Scintigraphy and Congo red staining, which demonstrated that CA is frequently misdiagnosed because of the low specific clinical manifestations and the results of imaging modalities that sometimes could be misleading, with subsequent delayed diagnosis and correct treatment.

| S-EPMC7596990 | biostudies-literature

Wild type transthyretin cardiac amyloidosis in a young individual: A case report.

Project description:RationaleSenile systemic amyloidosis, a disease of elderly is caused by amyloid deposition of wild-type transthyretin. The symptoms often overlap with other heart diseases. Hence it is either misdiagnosed or considered as a normal aging process in majority of cases.Patient concernsWe present a young patient of wild-type transthyretin amyloidosis, contradicting its only senile presence. The 34-year-old man presented with dyspnoea on exertion. He was suffering from hypertension for consecutive 3 years.DiagnosisEchocardiography demonstrated left ventricular hypertrophy with reduced global longitudinal strain and apical sparing. Congo red staining and immuno-histochemical staining of the abdominal fat biopsy confirmed transthyretin amyloid deposition. Genetic analysis revealed absence of any mutant variant/s of transthyretin gene, confirming wild-type transthyretin amyloidosis.InterventionA combination of amlodipine 5 mg, telmisartan 40 mg, and chlorthalidone 12.5 mg once daily was given to control the blood pressure of the patient.OutcomeBlood pressure was controlled but he continued to have exertional dyspnoea. The patient expired in December 2019.LessonsA systematic diagnosis for wild type transthyretin amyloid cardiomyopathy (ATTR-CM) shall be considered in young cardiac patients suffering from cardiac distress with unknown etiology.

| S-EPMC8084012 | biostudies-literature

Multimodality assessments of wild-type transthyretin cardiac amyloidosis with no ventricular hypertrophy.

Project description:While patients with transthyretin cardiac amyloidosis (ATTR-CA) typically present with concentric or asymmetric hypertrophy, a small percentage of ATTR-CA is known to present with 'atypical' cardiac morphologies such as eccentric hypertrophy or even no hypertrophy. However, detailed report of multimodality assessments of ATTR-CA with no ventricular hypertrophy is lacking. Herein, we report detailed multimodality assessments of an 81-year-old Japanese woman with heart failure and history of carpal tunnel syndrome and lumbar canal stenosis, presenting no ventricular hypertrophy and negative 99m technetium-pyrophosphate scintigraphy, who was eventually diagnosed as having wild-type ATTR-CA. Our case highlights the role of multimodality assessments for early diagnosis of ATTR-CA in patients with atypical cardiac morphologies and also emphasizes the limitations of bone scintigraphy and the importance of considering ATTR-CA in patients with non-cardiac manifestations of ATTR amyloidosis.

| S-EPMC10053176 | biostudies-literature

Wild-type transthyretin cardiac amyloidosis (ATTRwt-CA), previously known as senile cardiac amyloidosis: clinical presentation, diagnosis, management and emerging therapies.

Project description:Cardiac amyloidosis is thought to be a rare group of diseases caused by extracellular deposition of misfolded proteins in the extracellular cardiac matrix resulting in heart failure with preserved ejection fraction (HFpEF). This review focuses on the similarities and differences between the pathophysiology, clinical presentation and diagnostic tests of wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) compared to immunoglobulin light chain amyloidosis and hereditary cardiac amyloidosis. We address some obstacles to timely diagnosis and opportunities for management of the clinical symptoms as well as possibility of future novel disease modifying therapies.

| S-EPMC5906256 | biostudies-literature

Sex Differences in Wild-Type Transthyretin Amyloidosis: An Analysis from the Transthyretin Amyloidosis Outcomes Survey (THAOS).

Project description:IntroductionWild-type transthyretin amyloidosis (ATTRwt amyloidosis) is a progressive disease resulting from the accumulation of wild-type transthyretin (TTR) amyloid fibrils, and is diagnosed primarily in males. This analysis examined sex differences in patients with ATTRwt amyloidosis from the Transthyretin Amyloidosis Outcomes Survey (THAOS).MethodsTHAOS is an ongoing, global, longitudinal, observational survey of patients with transthyretin amyloidosis, including both inherited and wild-type disease, and asymptomatic carriers of TTR mutations. THAOS data were analyzed to identify potential differences in demographic and clinical characteristics between males and females with ATTRwt amyloidosis (data cutoff: August 1, 2021).ResultsOf 1386 patients with ATTRwt amyloidosis, 84 (6%) were female and 1302 (94%) were male. Females had a higher median age at enrollment (80 vs. 78 years; p = 0.002) and symptom onset (75 vs. 73 years; p = 0.045) than males. Mean left ventricular (LV) ejection fraction was higher (53% vs. 48%; p = 0.001) and mean LV diastolic diameter lower (42 vs. 46 mm; p < 0.001) in females versus males, but sex was not identified as a predictor of LV mean wall thickness adjusted for height (beta coefficient - 0.22; p = 0.460) or a predominantly cardiac phenotype (odds ratio 1.60; p = 0.191). Modified polyneuropathy disability scores differed between groups (p < 0.001), with a larger proportion of scores ≥ IIIa among females (23% vs. 7%).ConclusionsFemales with ATTRwt amyloidosis in THAOS tended to present at a later age and showed signs of less severe cardiac impairment and more severe walking impairment.Trial registrationClinicalTrials.gov: NCT00628745.

| S-EPMC9381661 | biostudies-literature

Genetic variation of the transthyretin gene in wild-type transthyretin amyloidosis (ATTRwt).

Project description:Wild-type transthyretin amyloidosis (ATTRwt), typically diagnosed as congestive heart failure in elderly Caucasian men, features myocardial amyloid deposits of wild-type plasma protein transthyretin (TTR). ATTRwt is sporadic, its pathogenesis is poorly understood, and currently there are no biomarkers for diagnosis or prognosis. Genetic studies of variant-associated transthyretin amyloidosis have suggested that non-coding TTR gene variants modulate disease. We hypothesized that cis-acting regulatory elements in the TTR gene non-coding regions may modify expression, affecting ATTRwt onset and progression. We studied an ATTRwt cohort consisting of 108 Caucasian males ranging in age from 59 to 87 years with cardiomyopathy due to wild-type TTR deposition; results were compared to 118 anonymous controls matched by age, sex, and race. Four predicted non-coding regulatory regions and all exons in the TTR gene were sequenced using the Sanger method. Eleven common variants were identified; three variants were significantly associated with ATTRwt (p < 0.05), though only one, rs72922940, remained near significance (p corrected = 0.083) after multiple testing correction. Exon analyses demonstrated the occurrence of the p.G26S (G6S) polymorphism in 7 % of ATTRwt subjects and 12 % of controls; this variant was predicted to be a protective factor (p = 0.051). Four variants were significantly associated with age at onset and survival. In this first genetic study of a large, well-characterized cohort of ATTRwt, non-coding and coding variants associated with disease, age at onset, and survival were identified. Further investigation is warranted to determine the prevalence of these variants in ATTRwt, their regulatory function, and potential role in assessing disease risk.

| S-EPMC4282974 | biostudies-literature

Transthyretin cardiac amyloidosis.

Project description:Transthyretin cardiac amyloidosis (ATTR-CA) is an increasingly recognized cause of heart failure (HF) and mortality worldwide. Advances in non-invasive diagnosis, coupled with the development of effective treatments, have shifted ATTR-CA from a rare and untreatable disease to a relatively prevalent condition that clinicians should consider on a daily basis. Amyloid fibril formation results from age-related failure of homoeostatic mechanisms in wild-type ATTR (ATTRwt) amyloidosis (non-hereditary form) or destabilizing mutations in variant ATTR (ATTRv) amyloidosis (hereditary form). Longitudinal large-scale studies in the United States suggest an incidence of cardiac amyloidosis in the contemporary era of 17 per 100 000, which has increased from a previous estimate of 0.5 per 100 000, which was almost certainly due to misdiagnosis and underestimated. The presence and degree of cardiac involvement is the leading cause of mortality both in ATTRwt and ATTRv amyloidosis, and can be identified in up to 15% of patients hospitalized for HF with preserved ejection fraction. Associated features, such as carpal tunnel syndrome, can preceed by several years the development of symptomatic HF and may serve as early disease markers. Echocardiography and cardiac magnetic resonance raise suspicion of disease and might offer markers of treatment response at a myocardial level, such as extracellular volume quantification. Radionuclide scintigraphy with 'bone' tracers coupled with biochemical tests may differentiate ATTR from light chain amyloidosis. Therapies able to slow or halt ATTR-CA progression and increase survival are now available. In this evolving scenario, early disease recognition is paramount to derive the greatest benefit from treatment.

| S-EPMC9897687 | biostudies-literature

Identification of wild-type transthyretin cardiac amyloidosis in patients with carpal tunnel syndrome surgery (CACTuS).

Project description:AimsWild-type transthyretin cardiac amyloidosis (ATTRwt) is an infiltrative cardiomyopathy with a poor prognosis. The condition is associated with carpal tunnel syndrome (CTS), which often precedes the ATTRwt diagnosis by several years. The aim of the study was (i) to screen patients with a recent history of CTS for ATTRwt using red flags, (ii) to determine whether patients with screened ATTRwt had less advanced disease compared with patients with clinical ATTRwt, and (iii) to assess the sensitivity and specificity of known red flags in ATTRwt.Methods and resultsPatients aged ≥60 years at the time of CTS surgery were invited for screening. Red flags were defined as elevated biomarker levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) or cardiac troponin, an electrocardiogram pattern associated with ATTRwt, left ventricular hypertrophy (LVH), and impaired longitudinal strain with apical sparring. All patients with a red flag were referred for a diagnostic scintigraphy. Patients with ATTRwt diagnosed by screening were compared with patients with clinical ATTRwt (n = 51) matched by age, gender, and CTS surgery. Among the 120 enrolled subjects (mean age 74.5 years, 90% male), the suspicion of ATTR was raised in 67 (55.8%), and 10 (8.3%) were diagnosed with ATTRwt. Patients identified with ATTRwt were predominantly asymptomatic and had mildly elevated NT-proBNP, mildly increased LVH, preserved left ventricular ejection fraction, and systolic longitudinal function, which differed significantly from clinical ATTRwt controls (P < 0.001).ConclusionsThe study found an ATTRwt prevalence of 8.3% in a population of age and gender-selected patients with a recent history of CTS. The identified patients with ATTRwt had less structural and functional cardiac involvement than clinical ATTRwt controls.

| S-EPMC9871677 | biostudies-literature

Features of atrial fibrillation in wild-type transthyretin cardiac amyloidosis: a systematic review and clinical experience.

Project description:AimsWild-type transthyretin (ATTRwt) cardiac amyloidosis has emerged as an important cause of heart failure in the elderly. Atrial fibrillation (AF) commonly affects older adults with heart failure and is associated with reduced survival, but its role in ATTRwt is unclear. We sought to explore the clinical impact of AF in ATTRwt.Methods and resultsPatients with biopsy-proven ATTRwt cardiac amyloidosis (n = 146) were retrospectively identified, and clinical, echocardiographic, and biochemical data were collected. Patients were classified as AF or non-AF and followed for survival for a median of 41.4 ± 27.1 months. Means testing, univariable, and multivariable regression models were employed. A systematic review was performed. AF was observed in 70% (n = 102). Mean age was similar (AF, 75 ± 6 vs. non-AF, 74 ± 5 years, P = 0.22). Anticoagulant treatment of patients with AF was as follows: 78% warfarin, 17% novel anticoagulant, and 6% no anticoagulation. Amiodarone was prescribed to 24%. There were no differences in left ventricular ejection fraction (P = 0.09) or left atrial volume (P = 0.87); however, mean diastolic dysfunction grade was higher in AF (mean 2.7 ± 0.5 vs. 2.4 ± 0.5, P = 0.01). While creatinine (P = 0.52) and B-type natriuretic peptide (P = 0.48) were similar, patients with AF had lower serum transthyretin concentrations (221 ± 51 vs. 250 ± 52 μg/mL, P < 0.01). Survival between groups was similar (P = 0.46).ConclusionsThese data provide an evidence basis for clinical management and demonstrate that AF in ATTRwt does not negatively impact survival. Further analysis of the relationship between transthyretin concentration and AF development is warranted.

| S-EPMC6165925 | biostudies-literature

Temporal Trends of Wild-Type Transthyretin Amyloid Cardiomyopathy in the Transthyretin Amyloidosis Outcomes Survey.

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

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