Transthyretin Amyloid Fibrils Research Articles

Sex Differences in Transthyretin Cardiac Amyloidosis: Unraveling the Complexities in Epidemiology, Pathophysiology, Diagnosis, and Treatment.

Transthyretin cardiac amyloidosis (ATTR-CA) is characterised by the deposition of transthyretin amyloid fibrils in the heart. ATTR-CA affects both men and women although there is evidence of sex differences in prevalence and clinical presentation. PURPOSE OF REVIEW: This review paper aims to comprehensively examine and synthesise the existing literature on sex differences in ATTR-CA. RECENT FINDINGS: The prevalence of ATTR-CA is higher in males although the male predominance is more apparent in older patients in the wild type form and in TTR genetic variants that predominantly result in a cardiac phenotype in the hereditary variant. Women tend to have less left ventricular hypertrophy (LVH) and a higher ejection fraction at clinical presentation which may contribute to a later diagnosis although the prognosis appears to be similar in both sexes. Female sex is a predictor of a good response to tafamidis 20mg in TTR polyneuropathy but otherwise there are no data on sex differences in the efficacy of other treatments for ATTR-CA. It is crucial to define specific sex differences in ATTR-CA. A lower cut-off value for LVH in women may be needed to improve diagnosis. It is necessary to increase female representation in clinical trials to better understand possible sex differences in therapeutic management.

A Comprehensive Review on Chemistry and Biology of Tafamidis in Transthyretin Amyloidosis.

Transthyretin amyloid cardiomyopathy and Transthyretin amyloid peripheral neuropathy are progressive disease conditions caused by Transthyretin amyloidosis (ATTR) fibril infiltration in the tissue. Transthyretin (TTR) protein misfolding and amyloid fibril deposits are pathological biomarkers of ATTR-related disorders. There are various treatment strategies targeting different stages in pathophysiology. One such strategy is TTR tetramer stabilization. Recently, a new TTR tetramer stabilizer, tafamidis, has been introduced that reduces the protein misfolding and amyloidosis and, consequently, disease progression in ATTR cardiomyopathy and peripheral neuropathy. This review will provide a comprehensive overview of the literature on tafamidis discovery, development, synthetic methods, pharmacokinetics, analytical methods and clinical trials. Overall, 7 synthetic methods, 5 analytical methods and 23 clinical trials have been summarized from the literature.

GI Amyloid: More Than a Heavy Heart

Amyloid transthyretin (ATTR) amyloidosis is caused by the accumulation of insoluble transthyretin (TTR) amyloid fibrils. These proteins can build up in various organ systems such as the musculoskeletal, gastrointestinal, and ocular system. However, there is usually a predilection for the heart and nervous system [1]. ATTR comprises approximately 16% of GI amyloid cases, with the small bowel being the most common area of involvement [2]. Symptoms typically include abdominal pain, nausea and vomiting, unintentional weight loss, diarrhea, and constipation. Given the rarity of the disease, we present a case of biopsy proven ATTR GI amyloidosis to raise awareness and, consequently, aid in early recognition. Our patient is a 48-year-old female with a medical history of substance use disorder who had multiple evaluations for complaints of chest discomfort and gastrointestinal symptoms including nausea, vomiting and diarrhea. Initial evaluation included an echocardiography which found severe left ventricular hypertrophy. Given her significant family history of myocardial infarction, a left cardiac catheterization was completed, however, this revealed normal coronary vasculature. Subsequently, the patient started medical therapy for heart failure with preserved ventricular function pending further testing. Despite medical management, the patient developed worsening symptoms of heart failure warranting repeat echocardiography which showed a significant reduction in ejection fraction. In addition to the patient's worsening cardiac symptoms, she continued to have refractory gastrointestinal symptoms and developed new epigastric pain. Therefore, the patient underwent upper endoscopy with discovery of abnormal peristalsis. After which, a gastric emptying study was done, resulting in a diagnosis of gastroparesis. With the constellation of findings i.e., the pattern of ventricular hypertrophy, lack of hypertensive and coronary artery disease, as well as gastroparesis without a known etiology, there was suspicion for systemic infiltrative disease, which led to further investigation. Gastric, small, and large bowel biopsies confirmed amyloid deposits. The patient also underwent a Tc99m-PYP scan which revealed evidence of cardiac amyloidosis; monoclonal protein analysis test was negative, and a cardiac biopsy showed a profile consistent with amyloid transthyretin type. The patient remained on pharmacologic therapy for gastroparesis and has been referred to cardiac transplantation services for further management.Our case highlights that amyloidosis, including GI amyloidosis, has the potential to go unrecognized due to non-specific signs and symptoms. Clinicians should therefore always have a high index of suspicion as GI involvement in systemic amyloidosis, regardless of protein subtype, is common. This high index of suspicion will allow for the appropriate pathologic examination to be pursued, and ultimately the appropriate management.

A 15-year consolidated overview of data in over 6000 patients from the Transthyretin Amyloidosis Outcomes Survey (THAOS)

BackgroundTransthyretin amyloidosis (ATTR amyloidosis) is a progressive, multisystemic, life-threatening disease resulting from the deposition of variant or wild-type (ATTRwt amyloidosis) transthyretin amyloid fibrils in various tissues and organs.MethodsEstablished in 2007, the Transthyretin Amyloidosis Outcomes Survey (THAOS) is the largest ongoing, global, longitudinal, observational study of patients with ATTR amyloidosis, including both hereditary and wild-type disease, and asymptomatic carriers of pathogenic TTR mutations. This analysis describes the baseline characteristics of symptomatic patients and asymptomatic gene carriers enrolled in THAOS since its inception in 2007 (data cutoff: August 1, 2022), providing a consolidated overview of 15-year data from the THAOS registry.ResultsThis analysis included 4428 symptomatic patients and 1707 asymptomatic gene carriers. The majority of symptomatic patients were male (70.8%) with a mean (standard deviation [SD]) age at symptom onset of 56.6 (17.9) years. Compared with the 14-year analysis, V30M remained the most prevalent genotype in Europe (62.2%), South America (78.6%), and Japan (74.2%) and ATTRwt remained most common in North America (56.2%). Relative to the 14-year analysis, there was an increase of mixed phenotype (from 16.6 to 24.5%) and a reduction of predominantly cardiac phenotype (from 40.7 to 31.9%). The proportion of patients with predominantly neurologic phenotype remained stable (from 40.1 to 38.7%). Asymptomatic gene carriers were 58.5% female with a mean age at enrollment of 41.9 years (SD 15.5).ConclusionsThis overview of > 6000 patients enrolled over 15 years in THAOS represents the largest registry analysis of ATTR amyloidosis to date and continues to emphasize the genotypic and phenotypic heterogeneity of the disease. Nearly a quarter of the symptomatic population within THAOS was mixed phenotype, underscoring the need for multidisciplinary management of ATTR amyloidosis.Trial registrationClinicalTrials.gov Identifier: NCT00628745.

Advanced echocardiographic assessment in wild-type and hereditary transthyretin cardiac amyloidosis: the role of myocardial work and left atrial strain

Abstract Introduction Transthyretin cardiac amyloidosis (ATTR-CA) is a progressive infiltrative cardiomyopathy caused by extracellular deposition of insoluble transthyretin (TTR) amyloid fibrils in the myocardium. ATTR-CA can be classified as wild type ATTR-CA (ATTRwt-CA), caused by age-related misfolding of TTR, and hereditary ATTR-CA (ATTRv-CA), an autosomal dominant disease in which gene mutations lead to changes in TTR protein. Speckle tracking echocardiography and myocardial work (MW) analysis can better characterize left ventricular and left atrial (LA) function in ATTRwt-CA and in ATTRv-CA. Aims to investigate differences in myocardial work and left atrial strain parameters between patients affected by ATTRwt-CA and patients affected by ATTRv-CA. Material and methods 40 male patients affected by ATTR-CA were prospectively enrolled, distinguishing between 20 patients with ATTRwt-CA (76 ± 7 yrs) and 20 patients with ATTRv-CA (74 ± 6 yrs) (1 pts with Val30Met mutation, 6 pts with Val122Ile mutation; 8 pts with Glu89Gln mutation; 5 pts with Phe64Leu mutation). All underwent a transthoracic echcoardiogram to calculate global longitudinal strain (GLS), MW parameters and LA strain. Results No difference was found between the two groups (ATTRwt-CA vs ATTRv-CA) for what regards age (76 ± 7 vs 74 ± 6 yrs, p = 0,06), BMI (27,2 ± 2,2 vs 26,6 kg/mq; p = 0,3), BSA (1,8 ± 0,2 vs 1,7 ± 0,1 mq; p = 0,1) and left ventricle mass index (LVMi) (183,41 ± 45,2 vs 148,5 ± 47,3 g/mq; p = 0,07). In ATTRwt-CA patients, ejection fraction (EF) is lower, but without any statistical significance (50 ± 6,9 vs 54 ± 6,4 %, p = 0,06). On the other hand, in ATTRwt-CA patients GLS is significantly higher than in ATTRv-CA patients (-9,8 ± 3,2 vs -15,0 ± 2,5 %; p < 0,0001). Global work index (GWI) (853,6 ± 367,6 vs 1431,6 ± 318,3 mmHg%; p < 0,0001), global constructive work (GCW) (1169 ± 303 vs 1726,5 ± 310,3 mmHg %; p < 0,0001) and global work efficiency (GWE) (83,2 ± 9,4 vs 89 ± 5,3 %; p = 0,04) are significantly reduced in ATTRwt-CA in comparison with ATTRv-CA. For what regards atrial function, in ATTwt-CA patients LA reservoir (9,7 ± 3,7 vs 17,6 ± 7,5 %; p = 0,004) and LA ejection fraction (LAFE) (28,9 ± 13,6 vs 46,2 ± 8,9; p = 0,02) are reduced, while LA booster is higher (-2,5 ± 3,1 vs -10 ± 4,7 %; p < 0, 0001). Conclusion In patients with ATTR-CA advanced echocardiographic assessment can better differentiate left atrial and left ventricular involvement in ATTRwt-CA versus ATTRv-CA.TablesGraphs

Design and Rationale the SCAN-MP (Screening for Cardiac Amyloidosis With Nuclear Imaging in Minority Populations) Study.

Background Transthyretin amyloid cardiomyopathy (ATTR-CM) is an important cause of heart failure in older individuals. Misfolding and deposition of transthyretin or prealbumin protein causes ATTR-CM in the context of a normal (wild-type) or variant TTR sequence. Variant ATTR-CM is most commonly caused by the substitution of valine for isoleucine at position 122 in transthyretin (Val122Ile or pV142I, almost exclusively observed in individuals of West African ancestry), demonstrated in 3.4% of self-identified Black individuals in the United States with an estimated 1.5 million carriers. Despite the large number of known pV142I carriers, the proportion of older Black patients with heart failure attributable to ATTR-CM remains unknown. Methods To address this knowledge gap, the SCAN-MP (Screening for Cardiac Amyloidosis with Nuclear Imaging in Minority Populations) study was funded by the National Institutes of Health/National Heart, Lung, and Blood Institute (R01HL139671) to enroll a targeted population of self-identified, community-dwelling Black or Caribbean Hispanic patients (many of whom are of West African ancestry) >60 years of age with heart failure and identify ATTR-CM by noninvasive nuclear imaging. The principal objective of SCAN-MP is to determine the prevalence of ATTR-CM in this population. Secondary objectives will explore TTR genotype, demographics, progression of variant versus wild-type ATTR-CM, and biochemical mechanisms of transthyretin amyloid fibril formation. Conclusions The SCAN-MP study is the largest, prospective study of cardiac amyloidosis in Black and Hispanic individuals. Both wild-type and variant ATTR-CM are now treatable with the US Food and Drug-approved drug tafamidis. The insights gained from SCAN-MP are likely to improve those at risk for or afflicted with ATTR-CM. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03812172.

Transthyretin (Pro24Ser) variant amyloidosis: A case report of the first patient in Greece.

Transthyretin cardiac amyloidosis (ATTR-CA) is a rare and potentially fatal disease caused by the accumulation of insoluble transthyretin (TTR) amyloid fibrils in the heart. The symptoms of ATTR-CA are often non-specific, often leading to underdiagnosis. Early diagnosis and treatment have a significant impact on disease progression and mortality. In this case we report a 73-year-old male presented with dyspnea on exertion. The patient had a medical history of peripheral neuropathy, bilateral carpal tunnel syndrome, spinal fusion, and a family history of coronary artery disease. Upon his presentation at the Cardiology department, cardiac echo study revealed left and right ventricular hypertrophy with pulmonary hypertension, diastolic dysfunction and a restrictive pattern. Because of the high probability of amyloidosis, the patient underwent a technetium-99m-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) bone scintigraphic study, which confirmed the diagnosis of ATTR-CA. Transthyretin gene sequencing analysis revealed the rare p. Pro24Ser pathogenic variant. Final diagnosis was ATTR-CA associated with the proline replaced by serine at position 24 (Pro24Ser) TTR variant, which is rare and only a few cases have been reported worldwide. The patient was treated with tafamidis and inotersen and followed up. This case highlights the importance of considering amyloidosis as a differential diagnosis for non-specific symptoms and the need for early diagnosis and management of ATTR-CA.

Characteristics of Patients with Hereditary Transthyretin Amyloidosis-Polyneuropathy (ATTRv-PN) in NEURO-TTRansform, an Open-label Phase 3 Study of Eplontersen.

Hereditary transthyretin (ATTRv) amyloidosis is a rare, severe, progressive, debilitating, and ultimately fatal disease caused by systemic deposition of transthyretin (TTR) amyloid fibrils. ATTRv amyloidosis occurs in both males and females. Eplontersen (ION-682884), a ligand-conjugated antisense oligonucleotide designed to degrade hepatic TTR mRNA, is being evaluated for the treatment of ATTRv amyloidosis with polyneuropathy (ATTRv-PN) in the phase 3, international, multicenter, open-label NEURO-TTRansform study (NCT04136184). To describe the study population of this pivotal trial, here we report the baseline characteristics of patients enrolled in the NEURO-TTRansform study. Patients eligible for NEURO-TTRansform were 18-82years old with a diagnosis of ATTRv-PN and Coutinho stage 1 (ambulatory without assistance) or stage 2 (ambulatory with assistance) disease; documented TTR gene variant; signs and symptoms consistent with neuropathy associated with ATTRv; no prior liver transplant; and New York Heart Association (NYHA) functional class I or II. The NEURO-TTRansform study enrolled 168 patients across 15 countries/territories (North America, 15.5%; Europe, 38.1%; South America/Australia/Asia, 46.4%). At baseline, the study cohort had a mean age of 52.8years, 69.0% of patients were male, and 78.0% of patients were White. The V30M variant was most prevalent (60.1% of patients), and prevalence varied by region. Overall, 56.5% and 17.3% of patients had received previous treatment with tafamidis or diflunisal, respectively. A majority of patients (79.2%) had Coutinho stage 1 disease (unimpaired ambulation) and early (before age 50) disease onset (53.0%). Time from diagnosis to enrollment was 46.6 (57.4) months (mean [standard deviation]). Most patients had a baseline polyneuropathy disability (PND) score of I (40.5%) or II (41.1%), and the mean modified Neuropathy Impairment Score + 7 (mNIS + 7) was 79.0. The recruited population in the ongoing NEURO-TTRansform study has global representation characteristic of contemporary clinical practice. ClinicalTrials.gov identifier NCT04136184.

960 EARLY ONSET OF SUBTLE LIVER DAMAGE IN TTR AMYLOIDOSIS PATIENTS TREATED WITH TAFAMIDIS

Abstract Background misfolded transthyretin amyloid fibrils can deposit in the myocardium causing transthyretin amyloid cardiomyopathy (ATTR-CM). Tafamidis has become recently available for the treatment of ATTR-CM, but to date very few data about its possible side effects have been published. Aims to investigate the potential liver toxicity of Tafamidis 61 mg/day in a group of patients affected by wild type ATTR-CM treated in our department. Materials and Methods 14 consecutive patients with wild-type ATTR-CM were treated with Tafamidis accordingly to the classical recommendations. The patients’ liver function was checked through transaminases and gammaGT determination at baseline and for the first six months and their changes analysed with the non-parametric Wilcoxon test for paired samples. Results mean age of the patients included (13 males and a female) was 78 years. Baseline transaminases were all within the normal range (median GOT level 25.0 U/L - IQR 19.0-29.0; median GPT levels 24.0 U/L - IQR 15.0-27.0) and remained stable for the first two months (median GOT at 2 months 25.5 U/L - IQR 19.0-28.0; median GPT at 2 months 22.5 U/L – IQR 16.0-27.0). Median GGT baseline level was 138.0 U/L (IQR 58.0-204.0) and raised to 142.0 U/L (IQR 56.0-270.0) after a two-month therapy (p<0.01). The further follow-up confirmed a similar trend in the first six month of treatment, with a linear and constant increase of gammaGT levels. Conclusions even not clinically relevant, the wild-type ATTR-CM patients included in our analysis showed all a subtle increase of gammaGT values after only two months of Tafamidis treatment, which was confirmed at six months. This observation underlines the potential hepatotoxicity of the drug, thus confirming the recommendations of strict and regular liver function analysis provided by the manufacturer.

Treating Transthyretin Amyloidosis via Adeno-Associated Virus Vector Delivery of Meganucleases.

Transthyretin amyloidosis (ATTR) is a progressive and fatal disease caused by transthyretin (TTR) amyloid fibril accumulation in tissues, which disrupts organ function. As the TTR protein is primarily synthesized by the liver, liver transplantation can cure familial ATTR but is not an option for the predominant age-related wild-type ATTR. Approved treatment approaches include TTR stabilizers and an RNA-interference therapeutic, but these require regular re-administration. Gene editing could represent an effective one-time treatment. We evaluated adeno-associated virus (AAV) vector-delivered, gene-editing meganucleases to reduce TTR levels. We used engineered meganucleases targeting two different sites within the TTR gene. AAV vectors expressing TTR meganuclease transgenes were first tested in immunodeficient mice expressing the human TTR sequence delivered using an AAV vector and then against the endogenous TTR gene in rhesus macaques. Following a dose of 3 × 1013 genome copies per kilogram, we detected on-target editing efficiency of up to 45% insertions and deletions (indels) in the TTR genomic DNA locus and >80% indels in TTR RNA, with a concomitant decrease in serum TTR levels of >95% in macaques. The significant reduction in serum TTR levels following TTR gene editing indicates that this approach could be an effective treatment for ATTR.

Extracellular Volume Fraction by Computed Tomography Predicts Long-Term Prognosis Among Patients With Cardiac Amyloidosis

BackgroundLight chain (AL) and transthyretin (ATTR) amyloid fibrils are deposited in the extracellular space of the myocardium, resulting in heart failure and premature mortality. Extracellular expansion can be quantified by computed tomography, offering a rapid, cheaper, and more practical alternative to cardiac magnetic resonance, especially among patients with cardiac devices or on renal dialysis. ObjectivesThis study sought to investigate the association of extracellular volume fraction by computed tomography (ECVCT), myocardial remodeling, and mortality in patients with systemic amyloidosis. MethodsPatients with confirmed systemic amyloidosis and varying degrees of cardiac involvement underwent electrocardiography-gated cardiac computed tomography. Whole heart and septal ECVCT was analyzed. All patients also underwent clinical assessment, electrocardiography, echocardiography, serum amyloid protein component, and/or technetium-99m (99mTc) 3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy. ECVCT was compared across different extents of cardiac infiltration (ATTR Perugini grade/AL Mayo stage) and evaluated for its association with myocardial remodeling and all-cause mortality. ResultsA total of 72 patients were studied (AL: n = 35, ATTR: n = 37; median age: 67 [IQR: 59-76] years, 70.8% male). Mean septal ECVCT was 42.7% ± 13.1% and 55.8% ± 10.9% in AL and ATTR amyloidosis, respectively, and correlated with indexed left ventricular mass (r = 0.426; P < 0.001), left ventricular ejection fraction (r = 0.460; P < 0.001), N-terminal pro–B-type natriuretic peptide (r = 0.563; P < 0.001), and high-sensitivity troponin T (r = 0.546; P < 0.001). ECVCT increased with cardiac amyloid involvement in both AL and ATTR amyloid. Over a mean follow-up of 5.3 ± 2.4 years, 40 deaths occurred (AL: n = 14 [35.0%]; ATTR: n = 26 [65.0%]). Septal ECVCT was independently associated with all-cause mortality in ATTR (not AL) amyloid after adjustment for age and septal wall thickness (HR: 1.046; 95% CI: 1.003-1.090; P = 0.037). ConclusionsCardiac amyloid burden quantified by ECVCT is associated with adverse cardiac remodeling as well as all-cause mortality among ATTR amyloid patients. ECVCT may address the need for better identification and risk stratification of amyloid patients, using a widely accessible imaging modality.

Change in echocardiography in patients with transthyretin amyloid cardiomyopathy with tafamidis treatment

Abstract Background Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive and infiltrative disease caused by the deposition of insoluble transthyretin (TTR) amyloid fibrils in the myocardium, which leads to cardiomyopathy characterized by increased ventricular wall thickness and diastolic dysfunction. TTR amyloid fibrils are performed by dissociation of the tetrameric TTR into monomers and misfolding and misassemble into insoluble fibrils. Tafamidis stabilizes the tetramers and inhibits the TTR monomerization, leads to inhibit the formation and deposition of TTR fibril. Clinical trials suggested tafamidis could improve prognosis by slowing the progression of amyloidosis. Evaluation of serial measurement echocardiographic findings by tafamidis treatment is important, but these data has not been fully revealed. Purpose The aim of study was to evaluate the change of echocardiographic parameter in patients with ATTR-CM received tafamidis for 12 months. Especially in strain echocardiogram, global longitudinal strain (GLS) has reported to be associated with prognosis, and apical sparing pattern, which longitudinal strain (LS) in the basal and middle segments is more severely impaired than the apical segments, is specific finding in ATTR-CM. Method Echocardiographic findings before and 12 months were compared in 68 patients with ATTR-CM who started a new prescription of tafamidis and 18 tafamidis naïve patients with ATTR-CM patients who underwent echocardiography annually prior to the approval of tafamidis. Result Among tafamidis treatment group, echocardiographic parameters were not significant changes before and after 12 months tafamidis treatment [left ventricular ejection fraction (LVEF): 49.6±10.6% vs. LVEF: 49.9±10.7% (p=0.767), interventricular septum diameter (IVSd):16.0±2.3mm vs 15.7±2.1mm (p=0.241), left ventricular posterior wall diameter (LVPWd):16.1±2.5mm vs 16.1±2.5mm (p=0.964), GLS: −8.4±2.7% vs −8.2±2.8% (p=0.419), LS at base: −4.6±2.6% vs −4.2±2.4% (p=0.291), LS at middle: −6.9±3.6% vs −6.9±2.8% (p=0.922), LS at apical:-12.7±4.2% vs −12.4±4.4% (p=0.615). Among tafamidis naïve group, these parameters remained almost unchanged in 12 months as well, except for GLS and LS at apical. LS at apical showed a significant impairment. [LVEF: 53.8±9.2% vs 51.7±9.3% (p=0.244), IVSd: 15.5±2.3mm vs 16.0±1.8mm (p=0.321), LVPWd: 15.4±2.3mm vs 15.9±2.3mm (p=0.267), GLS: −10.4±2.4% vs −9.0±2.9% (p=0.065), LS at base: −5.0±2.7% vs −5.1±2.9% (p=0.865), LS at middle: −8.9±3.1% vs −8.5±3.5% (p=0.565), LS at apical: −15.4±4.0% vs −12.6±4.4% (p=0.02); Table 1] Conclusion We evaluated changes in echocardiographic findings with tafamidis treatment for 12 months. The echocardiographic parameters did not change over the course of 12 months, but the decrease in LS at apex observed in the tafamidis naïve group.Segmental LS could reflect a slight progression of cardiac amyloidosis and the short-term effects of tafamidis. Funding Acknowledgement Type of funding sources: None.

Extracellular volume fraction by computed tomography predicts long-term prognosis among patients with cardiac amyloidosis

Abstract Objective This study sought to investigate the association of extracellular volume fraction by computed tomography (ECVCT), myocardial remodeling and mortality in patients with systemic amyloidosis. Background Light chain (AL) and transthyretin (ATTR) amyloid fibrils are deposited in the extracellular space of the myocardium, resulting in heart failure and premature mortality. Extracellular expansion can be quantified by CT, offering a rapid and cost-effective alternative to cardiovascular magnetic resonance (CMR), especially among patients with cardiac devices or on renal dialysis. Methods Patients with confirmed systemic amyloidosis and varying degrees of cardiac involvement underwent ECG-gated cardiac CT. ECVCT was analysed in the inter-ventricular septum. All patients also underwent clinical assessment, ECG, echocardiography, serum amyloid protein component (SAP) and/or technetium-99m (99mTc) 3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy. ECVCT was compared across different extents of cardiac infiltration (ATTR Perugini Grade / AL Mayo Class) and evaluated for its association with myocardial remodelling and all-cause mortality. Results 72 patients were studied (AL n=35, ATTR n=37; age 67 (59–76) years, 71% males). Mean septal ECVCT was 42.7±13.1% and 55.8±10.9% in AL and ATTR, respectively, and correlated with indexed left ventricular (LV) mass (r=0.426, p&amp;lt;0.001), LV ejection fraction [LVEF, (r=0.460, p&amp;lt;0.001)], NT-proBNP (r=0.563, p&amp;lt;0.001) and hsTnT (r=0.546, p=0.02). ECVCT increased with cardiac amyloid involvement in both AL and ATTR (Figure 1). Over a mean follow-up of 5.3±2.4 years, 40 deaths occurred (AL 14 [35%]; ATTR 26 [65%]). ECVCT was independently associated with all-cause mortality in ATTR (not AL) after adjustment for age and IV septal wall thickness (HR: 1.046, 95% CI: 1.003–1.090, p=0.037). Conclusion Cardiac amyloid burden quantified by ECVCT is associated with adverse cardiac remodelling as well as all-cause mortality among ATTR amyloid patients. ECVCT may address the need for better identification and risk stratification of amyloid patients, using a widely-accessible imaging modality (Figure 2). Funding Acknowledgement Type of funding sources: None.

Clinical and genetic profile of patients enrolled in the Transthyretin Amyloidosis Outcomes Survey (THAOS): 14-year update

BackgroundTransthyretin amyloidosis (ATTR amyloidosis) is a rare, life-threatening disease caused by the accumulation of variant or wild-type (ATTRwt amyloidosis) transthyretin amyloid fibrils in the heart, peripheral nerves, and other tissues and organs.MethodsEstablished in 2007, the Transthyretin Amyloidosis Outcomes Survey (THAOS) is the largest ongoing, global, longitudinal observational study of patients with ATTR amyloidosis, including both inherited and wild-type disease, and asymptomatic carriers of pathogenic TTR mutations. This descriptive analysis examines baseline characteristics of symptomatic patients and asymptomatic gene carriers enrolled in THAOS since its inception in 2007 (data cutoff: August 1, 2021).ResultsThis analysis included 3779 symptomatic patients and 1830 asymptomatic gene carriers. Symptomatic patients were predominantly male (71.4%) and had a mean (standard deviation [SD]) age of symptom onset of 56.3 (17.8) years. Val30Met was the most common genotype in symptomatic patients in South America (80.9%), Europe (55.4%), and Asia (50.5%), and more patients had early- versus late-onset disease in these regions. The majority of symptomatic patients in North America (58.8%) had ATTRwt amyloidosis. The overall distribution of phenotypes in symptomatic patients was predominantly cardiac (40.7%), predominantly neurologic (40.1%), mixed (16.6%), and no phenotype (2.5%). In asymptomatic gene carriers, mean (SD) age at enrollment was 42.4 (15.7) years, 42.4% were male, and 73.2% carried the Val30Met mutation.ConclusionsThis 14-year global overview of THAOS in over 5000 patients represents the largest analysis of ATTR amyloidosis to date and highlights the genotypic and phenotypic heterogeneity of the disease.ClinicalTrials.gov Identifier: NCT00628745.

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

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.

Prevalence, characteristics, and mortality of patients with transthyretin amyloid cardiomyopathy in the Nordic countries.

AimsTransthyretin amyloid cardiomyopathy (ATTR‐CM) is a progressive condition caused by deposition of transthyretin amyloid fibrils in the heart and is associated with poor quality of life and a shortened lifespan. This study aimed to describe the prevalence, clinical characteristics, and mortality of patients with ATTR‐CM, using multiple national health registers in Denmark, Finland, Norway, and Sweden.Methods and resultsTransthyretin amyloid cardiomyopathy patients were identified during 2008–2018 using a combination of diagnosis codes for amyloidosis and heart disease and were matched to patients with non‐ATTR heart failure (HF). An identical study design was used in each country to facilitate comparison and aggregation of results. A total of 1930 ATTR‐CM patients were identified from national health registers in the four countries. In 2018, prevalence of ATTR‐CM per 100 000 inhabitants ranged from 1.4 in Denmark to 5.0 in Sweden; a steep increase over time was observed in Sweden and Norway. Median survival from diagnosis was 30 months for ATTR‐CM patients and 67 months for matched HF patients. Survival was significantly lower for female than for male ATTR‐CM patients (median survival: 22 and 36 months), while no significant difference was observed in the HF cohort.ConclusionsThis study provides the first nationwide estimates of the prevalence, clinical characteristics, and mortality of patients with ATTR‐CM, using identical study design across several countries. Findings corroborate previous case series showing high mortality in ATTR‐CM, two‐fold higher than for other HF patients and higher in women than men, highlighting the need for more precise and early diagnosis to reduce the disease burden.

Targeted Therapeutics for Transthyretin Amyloid Cardiomyopathy.

Deposition of wild-type or mutant transthyretin (TTR) amyloid fibrils in the myocardium causes TTR amyloid cardiomyopathy (ATTR-CM). Targeted therapeutics for ATTR-CM include TTR stabilizers (tafamidis and diflunisal) and oligonucleotide drugs (revusiran, patisiran, and inotersen). TTR stabilizers prevent dissociation of transthyretin tetramers. Transthyretin monomers can misfold and form amyloid fibrils. TTR stabilizers thereby limit amyloid fibrils development and deposition. Oligonucleotide drugs inhibit hepatic synthesis of transthyretin, which decreases transthyretin protein levels and thus the amyloid fibril substrate. To study the safety and efficacy of targeted therapeutics in patients with ATTR-CM, we performed a pooled analysis. A random-effects model with the Mantel-Haenszel method was used to pool the data. A literature search was performed using PubMed, Cochrane CENTRAL, and Embase databases using the search terms "cardiac amyloidosis" AND "tafamidis" OR "patisiran" OR "inotersen" OR "revusiran" OR "diflunisal." We identified 6 studies that compared targeted therapeutics with placebo. One study was stopped prematurely because of increased mortality in the targeted therapeutics arm. Pooled analysis included 1238 patients, of which 738 patients received targeted therapeutics and 500 patients received placebo. When compared with placebo, targeted therapeutics significantly reduced all-cause mortality [OR 0.39, 95% confidence interval (CI): 0.16-0.97, P = 0.04]. Only 2 studies reported the effect on cardiovascular-related hospitalizations. There was a trend toward an improvement in global longitudinal strain (mean difference -0.69, 95% CI: -1.44 to 0.05, P = 0.07). When compared with placebo, there was no increase in serious adverse events with targeted therapeutics (OR 1.06, 95% CI: 0.78-1.44, P = 0.72). Evidence from the pooled analysis revealed targeted therapeutics improve survival and are well-tolerated. These findings suggest a potential role for targeted therapeutics in the treatment of patients with ATTR-CM.

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

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)

Nationwide prevalence and characteristics of transthyretin amyloid cardiomyopathy in Sweden

ObjectiveTransthyretin amyloid cardiomyopathy (ATTR-CM) is a rare, progressive and fatal condition caused by deposition of transthyretin amyloid fibrils in the heart. This study aims to identify all patients diagnosed with...

Sex-Related Risk of Cardiac Involvement in Hereditary Transthyretin Amyloidosis: Insights From THAOS

ObjectivesBecause patients with ATTRv cardiomyopathy are more likely to be male, this analysis aimed to increase information on associations between sex and genotype, phenotype, and degree of myocardial involvement in ATTRv amyloidosis. BackgroundTransthyretin amyloid cardiomyopathy is a progressive, fatal disease that occurs due to accumulation of wild-type or variant (ATTRv) transthyretin amyloid fibrils in the myocardium. MethodsThe Transthyretin Amyloidosis Outcomes Survey (THAOS) is an ongoing global longitudinal observational survey of patients with ATTR amyloidosis and asymptomatic carriers with TTR mutations. Data from THAOS (data cutoff: January 6, 2020) were analyzed to determine any sex-based differences in genotype, phenotype, and presence of cardiac and neurological symptoms in patients with ATTRv amyloidosis and in patients with ATTRv amyloidosis and cardiomyopathy. ResultsThere were 2,790 patients with ATTRv amyloidosis enrolled in THAOS, with male patients more likely to have symptoms of cardiac involvement and a cardiac phenotype. Male prevalence was greater in patients with more severe cardiac manifestations of disease, as assessed with N-terminal pro–B-type natriuretic peptide, left-ventricular (LV) ejection fraction, mean LV wall thickness divided by height, and LV mass index divided by height. Sex, age at disease onset, and genotype category were identified by multivariate analyses as risk factors for the development of cardiomyopathy (defined as increased LV septum thickness divided by height). ConclusionsIn this analysis, myocardial involvement was more frequent and pronounced in male patients with ATTRv amyloidosis, suggesting that there may be biological characteristics that inhibit myocardial amyloid infiltration in females or facilitate it in males.