Prospective Multicenter Screening With High-Sensitivity Cardiac Troponin T for Wild-Type Transthyretin Cardiac Amyloidosis in Outpatient and Community-Based Settings.

BACKGROUND: High-sensitivity cardiac troponin T (hs-cTnT) was proposed as a simple and useful diagnostic tool for cardiac amyloidosis (CA). We performed exploratory systemic screening using hs-cTnT to detect wild-type transthyretin CA (ATTRwt-CA) in outpatient and community-based settings. METHODS AND RESULTS: This study was a prospective multicenter study including 8 internal medicine clinics in Kochi Prefecture, Japan. Consecutive individuals aged ≥70 years who visited those clinics as outpatients were enrolled. Patients with a prior diagnosis of CA or a history of heart failure hospitalization were excluded. We measured hs-cTnT levels in the enrolled individuals at each clinic, and those with elevated hs-cTnT levels (≥0.03ng/mL) received further detailed examination, including remeasurement of hs-cTnT. The diagnosis of ATTRwt-CA was confirmed by biopsy-proven transthyretin. Of 1,141 individuals enrolled in the study, 55 (4.8%) had elevated hs-cTnT levels. Of the 33 patients who underwent further examination, 22 had elevated hs-cTnT levels at remeasurement. Finally, 2 men were diagnosed with ATTRwt-CA. The prevalence of ATTRwt-CA was 9.1% (2/22) among patients with elevated hs-cTnT levels at two examinations, and at least 0.18% (2/1,141) in the whole study population. CONCLUSIONS: Measurement of hs-cTnT will help to screen for patients with undiagnosed ATTRwt-CA in primary care practice.

DPD Quantification Correlates With Extracellular Volume and Disease Severity in Wild-Type Transthyretin Cardiac Amyloidosis.

Background: The pathophysiological hallmark of wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) is the deposition of amyloid within the myocardium. Objectives: This study aimed to investigate associations between quantitative cardiac 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) uptake and myocardial amyloid burden, cardiac function, cardiac biomarkers, and clinical status in ATTRwt-CM. Methods: Forty ATTRwt-CM patients underwent quantitative DPD single photon emission computed tomography/computed tomography to determine the standardized uptake value (SUV) retention index, cardiac magnetic resonance imaging to determine extracellular volume (ECV) and cardiac function (RV-LS), and assessment of cardiac biomarkers (N-terminal prohormone of brain natriuretic peptide [NT-proBNP], troponin T) and clinical status (6-minute walk distance [6MWD], National Amyloidosis Centre [NAC] stage). ATTRwt-CM patients were divided into 2 cohorts based on median SUV retention index (low uptake: <5.19 mg/dL, n = 20; high uptake: ≥5.19 mg/dL, n = 20). Linear regression models were used to assess associations of the SUV retention index with variables of interest and the Mann-Whitney U or chi-squared test to compare variables between groups. Results: ATTRwt-CM patients (n = 40) were elderly (78.0 years) and predominantly male (75.0%). Univariable linear regression analyses revealed associations of the SUV retention index with ECV (r = 0.669, ß = 0.139, P < 0.001), native T1 time (r = 0.432, ß = 0.020, P = 0.005), RV-LS (r = 0.445, ß = 0.204, P = 0.004), NT-proBNP (log10) (r = 0.458, ß = 2.842, P = 0.003), troponin T (r = 0.422, ß = 0.048, P = 0.007), 6MWD (r = 0.385, ß = -0.007, P = 0.017), and NAC stage (r = 0.490, ß = 1.785, P = 0.001). Cohort comparison demonstrated differences in ECV (P = 0.001), native T1 time (P = 0.013), RV-LS (P = 0.003), NT-proBNP (P < 0.001), troponin T (P = 0.046), 6MWD (P = 0.002), and NAC stage (I: P < 0.001, II: P = 0.030, III: P = 0.021). Conclusions: In ATTRwt-CM, quantitative cardiac DPD uptake correlates with myocardial amyloid load, longitudinal cardiac function, cardiac biomarkers, exercise capacity, and disease stage, providing a valuable tool to quantify and monitor cardiac disease burden.

Importance of fourth heart sound and preserved left atrial function in wild-type transthyretin amyloidosis.

AIMS: A fourth heart sound (S4) was reported to be almost never present in patients with amyloid light-chain cardiomyopathy. There have been no reports on S4 in patients with wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM). This study aimed to clarify the clinical implications of S4 in patients with ATTRwt-CM. METHODS AND RESULTS: Seventy-six patients with ATTRwt-CM (mean age: 80.4 ± 5.4 years, 68 males) who had undergone phonocardiography (PCG) were retrospectively assessed. We measured S4 amplitude on digitally recorded PCG. S4 was considered to be present when its amplitude was 1.0 mm or greater on the PCG. Distinct S4 was defined as S4 with an amplitude of 2.0 mm or greater, which is usually recognizable by auscultation. According to the rhythm and presence or absence of S4, the patients were divided into three groups, namely, sinus rhythm (SR) with S4, SR without S4, and non-SR. Non-SR consisted of atrial fibrillation, atrial flutter, and atrial tachycardia. Thirty-six patients were in SR and the remaining 40 patients were in non-SR. In the 36 patients in SR, S4 was shown by PCG to be present in 17 patients (47%), and distinct S4 was recognized in 7 patients (19%) by auscultation. In patients who were in SR, those with S4 had higher systolic blood pressure (124 ± 15 vs. 99 ± 8 mmHg, P < 0.001), lower level of plasma B-type natriuretic peptide (308 [interquartile range (IQR): 165, 354] vs. 508 [389, 765] pg/mL, P = 0.034) and lower level of high-sensitivity cardiac troponin T (0.068 [0.046, 0.089] vs. 0.109 [0.063, 0.148] ng/mL, P = 0.042) than those without S4. There was no significant difference in left atrium (LA) volume index or LA reservoir strain between patients with S4 and without S4. Patients with S4 had more preserved LA systolic function than those without S4 (peak atrial filling velocity: 53 ± 25 vs. 34 ± 9 cm/s, P = 0.033; LA contractile strain: 4.1 ± 2.1 vs. 1.6 ± 2.0%, P = 0.012). Patients in SR without S4 had worse short-term prognosis compared with the other two groups (generalized Wilcoxon test, P = 0.033). CONCLUSIONS: S4 was present in 47% of the patients in SR with ATTRwt-CM. Patients in SR without S4 had more impaired LA systolic function than those in SR with S4. The absence of S4 portends a poor short-term prognosis in patients with ATTRwt-CM.

Challenges associated with managing treatment complications in an older patient with cardiac amyloidosis.

BACKGROUND: Amyloidosis, particularly wild-type transthyretin amyloidosis (ATTRwt), is an increasingly recognized cause of heart failure with preserved ejection fraction in the aging population. The complexity of managing ATTRwt in older patients underscores the necessity for individualized treatment approaches, yet clinical guidelines are lacking. This case report contributes to the understanding of ATTRwt management in the elderly, emphasizing the intricacies of medication tolerance and therapeutic decision-making. CASE PRESENTATION: An 83-year-old Korean man with a history of hypertension presented with dyspnea and peripheral edema. Investigations including electrocardiography, transthoracic echocardiography, cardiac magnetic resonance, and Technetium pyrophosphate scintigraphy led to a diagnosis of ATTRwt cardiac amyloidosis. Initial management with heart failure medications, including an angiotensin-converting enzyme inhibitor, diuretic, and mineralocorticoid receptor antagonist, was modified due to evolving clinical presentations, such as hypotension and onset of atrial fibrillation. Challenges included intolerance to beta-blockers and bleeding complications from direct oral anticoagulant therapy. The patient's treatment journey highlighted the need for personalized management strategies in older ATTRwt patients. CONCLUSIONS: This case illustrates the challenges in diagnosing and managing ATTRwt amyloidosis in the elderly, particularly the complexities in medication management due to the patient's age, comorbid conditions, and side effects. It underscores the importance of a tailored approach in managing ATTRwt in older populations and highlights the need for ongoing research and development of treatment strategies tailored to this demographic.

Transthyretin amyloid cardiomyopathy among patients with heart failure and preserved ejection fraction: the AMY score.

AIMS: Transthyretin 'wild-type' amyloid cardiomyopathy (ATTRwt-CM) is a differential diagnosis of heart failure with preserved ejection fraction (HFpEF). The clinical work-up for ATTRwt-CM is challenging. Considering a combination of clinical variables specific for ATTRwt-CM might aid in identifying patients at risk. METHODS AND RESULTS: Sixty patients (78 ± 6 years, 8% female) were diagnosed with ATTRwt-CM by endomyocardial biopsy. Preserved ejection fraction (LVEF >45%) was present in 41 of the patients. Those were 1:1 propensity score age- and sex-matched to a cohort of patients with HFpEF. ATTRwt-CM patients had less obesity (P = 0.01) and higher septal thickness (IVSd, P < 0.01) as well as more diastolic dysfunction (E/e', P < 0.01). On multivariable regression IVSd > 14 mm, E/e' > 14 and absence of obesity (P > 0.01 for all) were identified as predictors for ATTRwt-CM. A weighted point-based score was derived with IVSd > 14 mm = 1 point; absence of obesity = 2 points; and E/e' > 14 = 3 points. Area under the curve (AUC) for the summation score was 0.91 (0.84-0.97, P < 0.01) and a score of more than 3 points predicted ATTRwt-CM with good sensitivity (78%) and specificity (90%). The score was validated in an external cohort of 142 patients with ATTRwt-CM and 419 HFpEF patients showing sufficient accuracy (AUC 0.91, 0.88-0.94, P < 0.01). A value greater than 3 points demonstrated a high sensitivity (93%) and a negative predictive value of 97%. CONCLUSIONS: A score based on basic clinical and echocardiographic features helps to distinguish ATTRwt-CM from typical HFpEF. This could facilitate the diagnostic work-up for these patients and enable earlier disease screening on a large scale.

Gait abnormalities in older adults with transthyretin cardiac amyloidosis.

BACKGROUND: Transthyretin cardiac amyloidosis (ATTR cardiac amyloidosis) is caused by variant (ATTRv) or wild type (ATTRwt) transthyretin. While gait abnormalities have been studied in younger patients with ATTRv amyloidosis, research on gait in older adults with ATTR cardiac amyloidosis is lacking. Given ATTR cardiac amyloidosis' association with neuropathy and orthopedic manifestations, we explore the gait in this population. METHODS: Twenty-eight older male ATTR cardiac amyloidosis patients and 11 healthy older male controls walked overground with and without a dual cognitive task. Gait parameters: stride width, length, velocity and stance time percentage were measured using an instrumented mat. ATTR amyloidosis patients were further categorized based on clinical and functional assessments. RESULTS: We found significant gait differences between ATTR cardiac amyloidosis patients and healthy controls; patients had more variable, slower, narrower and shorter strides, with their feet spending more time in contact with the ground as opposed to in swing. However, the observed gait differences did not correlate with clinical and functional measures of ATTR cardiac amyloidosis severity. CONCLUSIONS: Our results suggest that gait analysis could be a complementary tool for characterizing ATTR cardiac amyloidosis patients and may inform clinical care as it relates to falls, management of anticoagulation, and functional independence.

Hereditary transthyretin amyloidosis: a comprehensive review with a focus on peripheral neuropathy.

Amyloidoses represent a group of diseases characterized by the pathological accumulation in the extracellular area of insoluble misfolded protein material called "amyloid". The damage to the tissue organization and the direct toxicity of the amyloidogenic substrates induce progressive dysfunctions in the organs involved. They are usually multisystem diseases involving several vital organs, such as the peripheral nerves, heart, kidneys, gastrointestinal tract, liver, skin, and eyes. Transthyretin amyloidosis (ATTR) is related to abnormalities of transthyretin (TTR), a protein that acts as a transporter of thyroxine and retinol and is produced predominantly in the liver. ATTR is classified as hereditary (ATTRv) and wild type (ATTRwt). ATTRv is a severe systemic disease of adults caused by mutations in the TTR gene and transmitted in an autosomal dominant manner with incomplete penetrance. Some pathogenic variants in TTR are preferentially associated with a neurological phenotype (progressive peripheral sensorimotor polyneuropathy); others are more frequently associated with restrictive heart failure. However, many mutations express a mixed phenotype with neurological and cardiological involvement. ATTRv is now a treatable disease. A timely and definite diagnosis is essential in view of the availability of effective therapies that have revolutionized the management of affected patients. The purpose of this review is to familiarize the clinician with the disease and with the correct diagnostic pathways in order to obtain an early diagnosis and, consequently, the possibility of an adequate treatment.

Targeted sequencing of selected functional genes in patients with wild-type transthyretin amyloidosis.

OBJECTIVE: Wild-type transthyretin (ATTRwt) amyloidosis is caused by the misfolding and deposition of the transthyretin protein (TTR) in the absence of mutations in the TTR gene. Studies regarding the variant form of ATTR amyloidosis (ATTRv) suggest that the presence of single-nucleotide polymorphisms (SNP) in genes other than the TTR, may influence the development of the disease. However, other genetic factors involved in the aetiopathogenesis of ATTRwt are currently unknown. This work investigates the presence of sequence variants in genes selected for their possible impact on ATTRwt amyloidosis. To do so, targeted sequencing of 84 protein-coding genes was performed in a cohort of 27 patients diagnosed with ATTRwt. RESULTS: After applying quality and frequency filtering criteria, 72 rare or novel genetic variants were found. Subsequent classification according to the ACMG-AMP criteria resulted in 17 variants classified as of uncertain significance in 14 different genes. To our knowledge, this is the first report associating novel gene variants with ATTRwt amyloidosis. In conclusion, this study provides potential insights into the aetiopathogenesis of ATTRwt amyloidosis by linking novel coding-gene variants with the occurrence of the disease.

Wild-type transthyretin amyloid cardiomyopathy: expect the unexpected-a case report.

Background: General 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 summary: A 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. Discussion: The 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.

Machine Learning Approaches in Diagnosis, Prognosis and Treatment Selection of Cardiac Amyloidosis.

Cardiac amyloidosis is an uncommon restrictive cardiomyopathy featuring an unregulated amyloid protein deposition that impairs organic function. Early cardiac amyloidosis diagnosis is generally delayed by indistinguishable clinical findings of more frequent hypertrophic diseases. Furthermore, amyloidosis is divided into various groups, according to a generally accepted taxonomy, based on the proteins that make up the amyloid deposits; a careful differentiation between the various forms of amyloidosis is necessary to undertake an adequate therapeutic treatment. Thus, cardiac amyloidosis is thought to be underdiagnosed, which delays necessary therapeutic procedures, diminishing quality of life and impairing clinical prognosis. The diagnostic work-up for cardiac amyloidosis begins with the identification of clinical features, electrocardiographic and imaging findings suggestive or compatible with cardiac amyloidosis, and often requires the histological demonstration of amyloid deposition. One approach to overcome the difficulty of an early diagnosis is the use of automated diagnostic algorithms. Machine learning enables the automatic extraction of salient information from "raw data" without the need for pre-processing methods based on the a priori knowledge of the human operator. This review attempts to assess the various diagnostic approaches and artificial intelligence computational techniques in the detection of cardiac amyloidosis.

First Norwegian case of hereditary ATTR amyloidosis with a novel transthyretin variant.

An earlier healthy 64-year-old man with previous surgery for bilateral carpal tunnel syndrome (CTS) in his 50s, presented with dyspnoea on exertion. Cardiac amyloidosis was suspected due to "red flag" signs and symptoms. Further investigations with scintigraphy and genetic testing confirmed the diagnosis of hereditary ATTR variant (ATTRv) amyloidosis. This is the first case report of ATTRv amyloidosis in a patient of Norwegian origin and is caused by the mutation E54A (p.E74A) in the transthyretin (TTR) gene. This mutation is previously not reported in international databases. Transthyretin amyloid cardiomyopathy (ATTR-CM) is an underdiagnosed disease with a poor prognosis. Early recognition remains essential to afford the best treatment efficacy.

OCT angiography indices and the choroidal vascularity index in wild-type transthyretin (TTR) amyloidosis (ATTRwt).

Purpose: Retinal angiopathy represents a well-known ocular manifestation of hereditary transthyretin amyloidosis (ATTRv). Until recently, there have been no reports on retinal changes in ATTRwt. In this retrospective observational clinical study, we aimed to determine whether vessel density (VD) indices and the choroidal vascularity index (CVI) could offer insights into retinal and choroidal vascular changes among patients affected by ATTRwt. Methods: Eighteen patients with a confirmed diagnosis of ATTRwt underwent structural optical coherence tomography (OCT) and OCT angiography (OCTA). We established a control group consisting of 16 healthy subjects for statistical comparisons. The 3D OCT and OCTA datasets were analyzed to assess retinal and choroidal thickness and VD. For measuring CVI, we obtained measurements for the total choroid area (TCA), luminal area (LA), and stromal area (SA). Results: The mean VD exhibited a statistically significant reduction in the superficial capillary plexus (SCP), deep capillary plexus (DCP), and choriocapillaris (CC) among the ATTRwt group in comparison to the control group (p < 0.0001). Notably, ATTRwt patients displayed decreased choroidal thickness (p = 0.08). Additionally, the median CVI was lower in the ATTRwt group than in the control group (p = 0.04). Conclusion: The indices from OCTA and CVI have the potential to serve as non-invasive biomarkers for the quantitative evaluation of retinal and choroidal vascular involvement in patients with ATTRwt.

Low QRS Voltages in Cardiac Amyloidosis: Clinical Correlates and Prognostic Value.

Background: Low QRS voltages (LQRSVs) are a common electrocardiographic feature in patients with light chain amyloidosis (AL) and transthyretin amyloidosis (ATTR) cardiac amyloidosis (CA). Objectives: The aim of this study was to identify clinical and echocardiographic correlates of LQRSV and to investigate their prognostic significance in patients with CA. Methods: This was a multicenter, retrospective study performed in 6 CA referral centers including consecutive patients with AL and ATTR CA. LQRSVs were defined as a QRS amplitude ≤5 mm (0.5 mV) in all peripheral leads. The study outcome was cardiovascular (CV) mortality. Results: Overall, 411 (AL CA: n = 120, ATTR CA: n = 291) patients were included. LQRSVs were present in 66 (55%) patients with AL CA and 103 (35%) with ATTR CA (P < 0.001). In AL CA, LQRSVs were independently associated with younger age (P = 0.015), higher New York Heart Association functional class (P = 0.016), and natriuretic peptides (P = 0.041); in ATTR CA, LQRSVs were independently associated with pericardial effusion (P = 0.008) and lower tricuspid annulus peak systolic excursion (P = 0.038). During a median follow-up of 33 months (Q1-Q3: 21-46), LQRSVs independently predicted CV death in both AL CA (HR: 1.76; 95% CI: 2.41-10.18; P = 0.031) and ATTR CA (HR: 2.64; 95% CI: 1.82-20.17; P = 0.005). Together with the National Amyloidosis Centre (NAC) staging, LQRSVs provided incremental prognostic value in ATTR CA (AUC for NAC model: 0.83 [95% CI: 0.77-0.89]; AUC for NAC + LQRSV model: 0.87 [95% CI: 0.81-0.93]; P = 0.040). Conclusions: LQRSVs are common but not ubiquitous in CA; they are more frequent in AL CA than in ATTR CA. LQRSVs reflect an advanced disease stage and independently predict CV death. In ATTR CA, LQRSVs can provide incremental prognostic accuracy over the NAC staging system in patients with intermediate risk.

Prognosis of Transthyretin Cardiac Amyloidosis Without Heart Failure Symptoms.

Background: Transthyretin amyloid cardiomyopathy (ATTR-CM) is increasingly recognized as a treatable cause of heart failure (HF). Advances in diagnosis and therapy have increased the number of patients diagnosed at early stages, but prognostic data on patients without HF symptoms are lacking. Moreover, it is unknown whether asymptomatic patients benefit from early initiation of transthyretin (TTR) stabilizers. Objectives: The aim of this study was to describe the natural history and prognosis of ATTR-CM in patients without HF symptoms. Methods: Clinical characteristics and outcomes of patients with ATTR-CM without HF symptoms were retrospectively collected at 6 international amyloidosis centers. Results: A total of 118 patients (78.8% men, median age 66 years [IQR: 53.8-75 years], 68 [57.6%] with variant transthyretin amyloidosis, mean left ventricular ejection fraction 60.5% ± 9.9%, mean left ventricular wall thickness 15.4 ± 3.1 mm, and 53 [45%] treated with TTR stabilizers at baseline or during follow-up) were included. During a median follow-up period of 3.7 years (IQR: 1-6 years), 38 patients developed HF symptoms (23 New York Heart Association functional class II and 14 functional class III or IV), 32 died, and 2 required cardiac transplantation. Additionally, 20 patients received pacemakers, 13 developed AF, and 1 had a stroke. Overall survival was 96.5% (95% CI: 91%-99%), 90.4% (95% CI: 82%-95%), and 82% (95% CI: 71%-89%) at 1, 3, and 5 years, respectively. Treatment with TTR stabilizers was associated with improved survival (HR: 0.31; 95% CI: 0.12-0.82; P = 0.019) and remained significant after adjusting for sex, age, ATTR-CM type, and estimated glomerular filtration rate (HR: 0.18; 95% CI: 0.06-0.55; P = 0.002). Conclusions: After a median follow-up period of 3.7 years, 1 in 3 patients with asymptomatic ATTR-CM developed HF symptoms, and nearly as many died or required cardiac transplantation. Treatment with TTR stabilizers was associated with improved prognosis.

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

INTRODUCTION: Wild-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). METHODS: THAOS 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). RESULTS: Of 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%). CONCLUSIONS: Females 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 REGISTRATION: ClinicalTrials.gov: NCT00628745.

The Relationship Between Wild-Type Transthyretin Amyloid Load and Ligamentum Flavum Thickness in Lumbar Stenosis Patients.

BACKGROUND: One key contributor to lumbar stenosis is thickening of the ligamentum flavum (LF), a process still poorly understood. Wild-type transthyretin amyloid (ATTRwt) has been found in the LF of patients undergoing decompression surgery, suggesting that amyloid may play a role. However, it is unclear whether within patients harboring ATTRwt, the amount of amyloid is associated with LF thickness. METHODS: From an initial cohort of 324 consecutive lumbar stenosis patients whose LF specimens from decompression surgery were sent for analysis (2018-2019), 33 patients met the following criteria: 1) Congo red-positive amyloid in the LF, 2) ATTRwt by mass spectrometry-based proteomics, and 3) an available preoperative magnetic resonance imaging. Histological specimens were digitized, and amyloid load was quantified through Trainable Weka Segmentation machine learning. LF thicknesses were manually measured on axial T2-weighted preoperative magnetic resonance imaging scans at each lumbar level, L1-S1. The sum of thicknesses at every lumbar LF level (L1-S1) equals "lumbar LF burden". RESULTS: Patients had a mean age of 72.7 years (range = 59-87), were mostly male (61%) and white (82%), and predominantly had surgery at L4-L5 levels (73%). Amyloid load was positively correlated with LF thickness (R = 0.345, P = 0.0492) at the levels of surgical decompression. Furthermore, amyloid load was positively correlated with lumbar LF burden (R = 0.383, P = 0.0279). CONCLUSIONS: Amyloid load is positively correlated with LF thickness and lumbar LF burden across all lumbar levels, in a dose-dependent manner. Further studies are needed to validate these findings, uncover the underlying pathophysiology, and pave the way toward using therapies that slow LF thickening.

Suspicion, screening, and diagnosis of wild-type transthyretin amyloid cardiomyopathy: a systematic literature review.

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.

Hand surgeons and amyloidosis specialists warning: transthyretin-associated amyloidosis with bifid median nerve as a cause of bilateral carpal tunnel syndrome. A case report and literature review.

INTRODUCTION: Approximately 75% of patients with carpal tunnel syndrome (CTS) are diagnosed as idiopathic. Despite this, the presence of an underlying cause such as an anatomical variant or a systemic disease must always be suspected, especially in cases of bilateral presentation without an obvious cause, recurrence or complications. The anatomical variant known as the bifid median nerve (BMN) is a very rare abnormality that can occasionally lead to CTS. On the other hands, transthyretin-associated amyloidosis (ATTR) is one of the possible causes of bilateral CTS. We report a case where these two very rare pathologies converge as the cause of bilateral CTS and a review of the literature. CASE REPORT: We report a 71-year-old male with prior history of lumbar canal stenosis, bilateral trigger finger, rupture of the supraspinatus muscle tendon and of the long portion of the right biceps brachial. He also had 8-year-old bilateral CTS that recurred after CTS surgery. He was surgically re-intervened and was diagnosed incidentally with BMN and an ultrasound of the other hands also showed BMN. Because of all the prior musculoskeletal history, a biopsy of the transverse carpal ligament was taken showing ATTR deposits that led to the diagnosis of cardiac ATTR wild type. CONCLUSIONS: This case highlights the natural history of the multiple musculoskeletal manifestations related to ATTR and the importance of performing intraoperative biopsies in patients with CTS surgery as this can lead to early diagnosis of cardiac ATTR.

Concurrent cardiac transthyretin and brain ß amyloid accumulation among the older adults: The Hisayama study.

Previous studies have revealed risk for cognitive impairment in cardiovascular diseases. We investigated the relationship between degenerative changes of the brain and heart, with reference to Alzheimer's disease (AD) pathologies, cardiac transthyretin amyloid (ATTR) deposition, and cardiac fibrosis. A total of 240 consecutive autopsy cases of a Japanese population-based study were examined. ß amyloid (Aß) of senile plaques, phosphorylated tau protein of neurofibrillary tangles, and ATTR in the hearts were immunohistochemically detected and graded according to the NIH-AA guideline for AD pathology and as Tanskanen reported, respectively. Cerebral amyloid angiopathy (CAA) was graded according to the Vonsattel scale. Cardiac fibrosis was detected by picrosirius red staining, followed by image analysis. Cardiac ATTR deposition occurred after age 75 years and increased in an age-dependent manner. ATTR deposition was more common, and of higher grades, in the dementia cases. We subdivided the cases into two age groups: ≤90 years old (n = 173) and >90 years old (n = 67), which was the mean and median age at death of the AD cases. When adjusted for age and sex, TTR deposition grades correlated with Aß phase score (A2-3), the Consortium to Establish a Registry for AD score (sparse to frequent), and high Braak stage (V-VI) only in those aged ≤90 years at death. No significant correlation was observed between the cardiac ATTR deposition and CAA stages, or between cardiac fibrosis and AD pathologies. Collectively, AD brain pathology correlated with cardiac TTR deposition among the older adults ≤90 years.

Clinical and apparative investigation of large and small nerve fiber impairment in mixed cohort of ATTR-amyloidosis: impact on patient management and new insights in wild-type.

INTRODUCTION: Neuropathy in transthyretin (ATTR) amyloidosis is frequently underdiagnosed, delaying effective treatment. Early detection of large- and small-nerve fiber damage via a comprehensive diagnostic algorithm impacts on clinical management. METHODS: A mixed cohort of patients with ATTR amyloidosis (wild type-wt, hereditary-v and TTR gene mutation carriers) of the Interdisciplinary Amyloidosis Centre of Northern Bavaria underwent clinical examination, nerve conduction studies (NCS), quantitative sensory testing (QST), sympathetic skin response (SSR), quantitative sudomotor axon reflex testing (QSART), and skin punch biopsies. RESULTS: Out of 30 study participants (7 ATTRv/asymptomatic gene carriers, 23 ATTRwt) large-fiber neuropathy was found in 43% patients with ATTRv and 70% with ATTRwt. QST revealed a mixed small and large fiber impairment in all ATTRv/asymptomatic gene carriers and in 78% of ATTRwt. Autonomic tests were pathological in the majority of ATTRv and over 50% of ATTRwt patients. Skin biopsies (sampled from 19 patients) showed reduced intraepidermal nerve fiber density (IENFD) in all ATTRv/asymptomatic gene carriers and over 80% of ATTRwt. Two ATTRwt patients had a pure small fiber neuropathy. After reviewing for relevant co-morbidities, 44% of ATTRwt patients exhibited neuropathy (large and/or small fiber) without evidence of any other underlying cause. Disease manifestation in the peripheral nervous system was newly diagnosed in three ATTR gene mutation carriers, thereby influencing clinical management. CONCLUSION: This comprehensive test program gives new insights regarding the presence of neuropathy in ATTRv and ATTRwt, which impact on patient management.