Deposition Of Transthyretin Research Articles

Assessing the utility of the increased wall thickness score in diagnosing ATTR cardiomyopathy: a validation study

Abstract Introduction Cardiac amyloidosis due to transthyretin deposition (ATTR-CM) is often underdiagnosed. An increased left ventricular wall thickness (LVWT) should raise the suspicion for ATTR-CM, but it is a very frequent and non-specific finding. In order to improve diagnostic certainty, an echocardiographic score (Increased Wall Thickness [IWT] score) was recently proposed. The aim of our study was to assess the diagnostic performance of the IWT score in an independent population with increased LVWT. Methods We conducted a retrospective analysis of 295 consecutive patients studied at our centre for increased LVWT. All patients with severe aortic stenosis (AS) had ATTR-CM excluded by endomyocardial biopsy (EMB), during aortic valve replacement. ATTR-CM was considered as per the ESC algorithm. To be included, patients with Hypertrophic Cardiomyopathy (HCM) performed cardiac magnetic resonance and required a sarcomeric mutation for definite diagnosis. The echocardiographic IWT score was calculated for all patients, and categorized as certain (IWT≥8), unlikely (IWT ≤1) or indeterminate (1 < IWT < 8) for ATTR-CM diagnosis. Results A total of 295 patients were included (median age of 75 years [69-81], 61% men). Overall, 230 (70%) patients had hypertension and 164 (56%) chronic kidney disease (CKD). The median LVWT was 16 mm [IQR 15-19] and the median LVEF was 57% [IRQ 50-62%]. After diagnostic workup, 97 patients (33%) had confirmed ATTR-CM, 129 (44%) had isolated severe AS and 71 (24%) had hypertrophic cardiomyopathy (HCM). Fifteen patients had both severe AS and ATTR-CM. The median IWT score was 4 (IQR 2-7), with 21% of patients (n=64) showing an IWT score ≤1, 19% an IWT score ≥8, and 60% of patients (n=176) having an "indeterminate" value between 2 and 7. Despite this, on a continuous scale, the IWT showed good discriminative value (area under ROC curve 0.86, 95% 0.82-0.90, p<0.001). The criteria of IWT score ≥8 showed a positive predictive value of 82% (95% CI 72-89%), while an IWT score ≤ 1 yielded a negative predictive value of 92% (95% CI 84-97%) - Figure. Conclusions Even though the IWT score provides "indeterminate" results in a large proportion of patients, values at the ends of the spectrum showed good negative and positive predictive values for the diagnosis of ATTR-CM. Our findings provide external validation for this echocardiographic score, and support its use in the diagnostic workup of patients with increased wall thickness and suspected ATTR-CM.

Altered connectivity of central autonomic network: effects of dysautonomia in hereditary transthyretin amyloidosis with polyneuropathy

Background Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is a progressive fatal disorder caused by deposition of mutant transthyretin (TTR) amyloids mainly in the nerves and heart. Autonomic dysfunction is a major disabling manifestation, affecting 90% of patients with late-onset ATTRv-PN. The current study aimed to investigate brain functional alterations associated with dysautonomia due to peripheral autonomic nerve degeneration in ATTRv-PN. Methods Resting-state functional MRI data were acquired from 43 ATTRv-PN patients predominantly of A97S (p.A117S) genotype, and the functional connectivity of central autonomic regions was assessed. Results Compared with age-matched healthy controls, the ATTRv-PN patients exhibited (1) reduced functional connectivity of the central autonomic regions such as hypothalamus, amygdala, anterior insula, and middle cingulate cortex with brain areas of the limbic, frontal, and somatosensory systems, and (2) correlations of reduced functional autonomic connectivity with the severity of autonomic dysfunction especially orthostatic intolerance, decreased heart rate variability, and greater clinical disability. Conclusions Our findings provide evidence linking peripheral autonomic dysfunction with altered connectivity in the central autonomic network in ATTRv-PN.

Role of Multimodality Imaging in the Diagnostic work-up for Cardiac Amyloidosis

Cardiac amyloidosis is caused by the deposition of transthyretin or light-chain fibrils into the myocardium, leading to restrictive cardiomyopathy, and eventually death if untreated. The improvement in diagnostic modalities has seen a recent surge in the number of patients being diagnosed with cardiac amyloidosis, particularly transthyretin amyloidosis. The diagnostic workup often starts with echocardiogram, followed by cardiac magnetic resonance and finally pyrophosphate scintigraphy. It is important to know that while transthyretin amyloidosis is often diagnosed non-invasively with technetium pyrophosphate scan in the contemporary practice, the diagnosis of light-chain amyloidosis still needs tissue confirmation.

Structural polymorphism of amyloid fibrils in ATTR amyloidosis revealed by cryo-electron microscopy

ATTR amyloidosis is caused by the deposition of transthyretin in the form of amyloid fibrils in virtually every organ of the body, including the heart. This systemic deposition leads to a phenotypic variability that has not been molecularly explained yet. In brain amyloid conditions, previous studies suggest an association between clinical phenotype and the molecular structures of their amyloid fibrils. Here we investigate whether there is such an association in ATTRv amyloidosis patients carrying the mutation I84S. Using cryo-electron microscopy, we determined the structures of cardiac fibrils extracted from three ATTR amyloidosis patients carrying the ATTRv-I84S mutation, associated with a consistent clinical phenotype. We found that in each ATTRv-I84S patient, the cardiac fibrils exhibited different local conformations, and these variations can co-exist within the same fibril. Our finding suggests that one amyloid disease may associate with multiple fibril structures in systemic amyloidoses, calling for further studies.

Cardiac Amyloidosis: Approach to Diagnosis

Amyloid is an amorphous, fibrillar material formed from various abnormally folded proteins that deposits locally or systemically. Over 95% of cases have been attributed to light chain deposition (AL) or transthyretin deposition (ATTR) amyloidosis. The basic investigations in the evaluation of cardiac amyloidosis include the electrocardiogram, echocardiography and cardiac biomarkers. Echocardiography in a patient with cardiac amyloidosis shows biatrial enlargement, biventricular hypertrophy, diastolic dysfunction, interatrial septal thickening, valvular thickening, a glistening appearance of the interventricular septum, and pericardial effusion. Magnetic resonance imaging can help distinguish amyloidosis from other causes of infiltrative/restrictive cardiomyopathy, from example, sarcoidosis, hemochromatosis, and Fabry disease based on characteristic enhancement patterns in these diseases. The latest Expert Consensus recommends that serum/urine immunofixation electrophoresis along with a serum free light chain assay must be done in all the cases of suspected cardiac amyloidosis. If the light chain assays are positive, we proceed with tissue diagnosis for confirmation of AL amyloidosis. If the screening assays are negative for monoclonal gammopathy, the next step is to obtain cardiac scintigraphy. If the nuclear scan is negative, but the index of suspicion remains high, an endomyocardial biopsy can be done. Once amyloid is demonstrated in histopathologic specimens, it must be typed to distinguish between AL and ATTR. The ideal method for this is tandem mass spectrometry, although this may not be widely available. It has a sensitivity of 88% and specificity of 96% higher than other techniques 23. In resource-poor settings, immunohistochemistry or immunoelectron microscopy can allow this distinction, although with lesser sensitivity.

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

Evaluation of disease progression in patients with ATTR amyloidosis with cardiomyopathy following treatment with patisiran: post-hoc analysis of the APOLLO-B study

Abstract Introduction Transthyretin-mediated (ATTR) amyloidosis is a progressive, fatal disease in which cardiac deposition of transthyretin (TTR) amyloid commonly manifests as cardiomyopathy. Patisiran, an RNA interference therapeutic that reduces TTR synthesis, is approved for the treatment of hereditary ATTR amyloidosis with polyneuropathy. The Phase 3 APOLLO-B study (NCT03997383) evaluated the clinical efficacy and safety of patisiran in patients with ATTR amyloidosis with cardiomyopathy (CM). Purpose This post-hoc analysis evaluated disease progression in APOLLO-B patients following treatment with patisiran vs placebo, based on the European Society of Cardiology (ESC) expert consensus on monitoring patients with ATTR amyloidosis with CM every 6–12 months using three domains: Clinical/Functional, Laboratory Biomarker, and Imaging/Electrocardiography (ECG). Methods Patients with ATTR amyloidosis with CM were randomised (1:1) to intravenous patisiran 0.3 mg/kg or placebo every 3 weeks for 12 months. Disease progression was defined at Month 12 (M12) relative to baseline using Clinical/Functional criteria (≥1 heart failure-related hospitalisation, increased New York Heart Association class ≥1, decline in Kansas City Cardiomyopathy Questionnaire ≥5, or decline in 6-minute walk test ≥30 metres), Laboratory Biomarker criteria (increased N-terminal prohormone B-type natriuretic peptide ≥30% and absolute change ≥300 ng/L, troponin I ≥30%, or ATTR disease stage ≥1), and Imaging/ECG criteria (conduction disturbances or change in left ventricular wall thickness ≥2 mm, change in diastolic dysfunction grade ≥1, or change in systolic function measurements). One marker from each domain provides the minimum criteria for disease progression. Results At M12, the patisiran group (N = 180) had improved odds of no disease progression compared with the placebo group (N = 178; odds ratio [OR] 1.4; 95% confidence interval [CI] 0.77, 2.55) (Figure). The patisiran group had benefits in Clinical and Functional markers vs placebo at M12 (OR 1.58; 95% CI 1.03, 2.42). Patisiran also showed favourable changes in Laboratory Biomarkers vs placebo at M12 (OR 2.14; 95% CI 1.33, 3.43) and a favourable trend in Imaging assessments/ECG vs placebo at M12 (OR 1.31; 95% CI 0.80, 2.15). Conclusion In this post-hoc analysis of APOLLO-B, fewer patisiran-treated patients had disease progression with respect to clinical, functional, and biomarker parameters vs placebo. The risk of disease progression was lower by Clinical/Functional and Laboratory Biomarker composite criteria, and trended lower by individual criterion from the ESC consensus statement among patisiran-treated patients at 12 months vs placebo patients. Long-term follow-up will further assess the impact of patisiran in patients with ATTR amyloidosis with CM.Figure 1

Technetium-99m-pyrophosphate imaging-based computed tomography-guided core-needle biopsy of internal oblique muscle in wild-type transthyretin cardiac amyloidosis

Background Technetium-99m-pyrophosphate (99mTc-PYP) uptake in the internal oblique muscle (IOM), which is often observed in patients with wild-type transthyretin cardiac amyloidosis (ATTR-CA), indicates amyloid transthyretin (ATTR) deposition. Objective This study aimed to assess the safety and efficacy of 99mTc-PYP imaging-based computed tomography (CT)-guided core-needle biopsy of the IOM as a new extracardiac screening biopsy for confirming the presence of ATTR deposits. Methods Patients with suspected ATTR-CA in whom myocardial tracer uptake was detected on chest- and abdomen-centered images of 99mTc-PYP scintigraphy underwent CT-guided core-needle biopsy at the site with the highest tracer uptake in the IOM between September 2021 and November 2022. Results All 18 consecutive patients (mean age, 86.3 years ± 6.5; 61.1% male) enrolled in the study showed 99mTc-PYP uptake into the IOM. Adequate tissue samples were obtained from all patients except one without serious complications. Immunohistochemical analysis confirmed ATTR deposits in 16/18 (88.9%) patients. In the remaining two patients, ATTR deposits were observed via endomyocardial biopsy. All patients were diagnosed with wild-type ATTR-CA based on transthyretin gene sequence testing results. Conclusion In wild-type ATTR-CA, 99mTc-PYP imaging-based CT-guided core-needle biopsy of the IOM could be used as an extracardiac screening biopsy to confirm the presence of ATTR deposits.

Benziodarone and 6-hydroxybenziodarone are potent and selective inhibitors of transthyretin amyloidogenesis

Transthyretin amyloidosis is a progressive systemic disorder that is caused by the amyloid deposition of transthyretin in various organs. Stabilization of the native transthyretin is an effective strategy for the treatment of transthyretin amyloidosis. In this study we demonstrate that the clinically used uricosuric agent benziodarone is highly effective to stabilize the tetrameric structure of transthyretin. An acid-induced aggregation assay showed that benziodarone had strong inhibitory activity similar to that of tafamidis, which is currently used as a therapeutic agent for transthyretin amyloidosis. Moreover, a possible metabolite, 6-hydroxybenziodarone, retained the strong amyloid inhibitory activity of benziodarone. An ex vivo competitive binding assay using a fluorogenic probe showed that benziodarone and 6-hydroxybenziodarone were highly potent for selective binding to transthyretin in human plasma. An X-ray crystal structure analysis revealed that the halogenated hydroxyphenyl ring was located at the entrance of the thyroxine binding channel of transthyretin and that the benzofuran ring was located in the inner channel. These studies suggest that benziodarone and 6-hydroxybenziodarone would potentially be effective against transthyretin amyloidosis.

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.

Right ventricular-dominant transthyretin deposition: an early stage or a rare phenotype of wild-type transthyretin amyloid cardiomyopathy?

An 86-year-old Japanese man was referred to our hospital because of leg oedema. Electrocardiography revealed a right bundle branch block, and transthoracic echocardiography showed a left ventricular septal wall thickness of 15 mm. On cardiovascular magnetic resonance imaging (CMR), late gadolinium enhancement areas and high native T1 value areas extended in the basal region of the left ventricular lateral wall (Panels A and C), the right ventricular (RV) side of the septum, and the RV free wall (Panels B and D). Abnormal accumulation of 99mTc-labelled pyrophosphate (99mTc-PYP) in the myocardium was visualized in concordance with the abnormal areas on CMR (Panels E and F). The patient was diagnosed with wild-type transthyretin amyloid cardiomyopathy (ATTR-CM) due to the histological evidence of transthyretin deposition in the myocardium and no transthyretin gene mutation. In this case, both CMR and 99mTc-PYP scintigraphy, which are reliable imaging tools for transthyretin deposition in the myocardium, revealed RV-dominant transthyretin deposition. Based on the UK ATTR-CM staging system, this case was classified as Stage 1. Since no cases of RV-dominant transthyretin deposition have been reported in the literature, it is unclear whether RV-dominant transthyretin deposition is an early stage or a very rare clinical phenotype of wild-type ATTR-CM. Nonetheless, clinicians should be aware of an RV-dominant transthyretin deposition pattern in wild-type ATTR-CM.

Prevalence of Orthopedic Manifestations in Patients With Cardiac Amyloidosis With a Focus on Shoulder Pathologies

Transthyretin cardiac amyloidosis (ATTR-CA) is a restrictive cardiomyopathy that has been associated with multiple orthopedic pathologies years before it manifests in the heart. There have been no studies on the prevalence of a wide range of shoulder pathologies in patients with cardiac amyloidosis (CA). Due to the preferential deposition of transthyretin in the soft tissues and joints, we predicted a greater prevalence of shoulder pathologies and other orthopedic manifestations in patients with ATTR-CA. This single-center, retrospective, case-control study, analyzed 1,310 patients with CA, 830 with ATTR-CA, and 480 with light-chain CA (AL-CA) from a dedicated CA REDcap database. Odds ratios comparing patients with CA to the age-matched published estimate of over 300 million patients in the general population were determined for shoulder, hip, and knee arthroplasty. Years between a patient's first shoulder pathology (i.e., shoulder arthroplasty) and the year of their diagnosis with CA were determined using data from patients with a known date of surgery. Overall, patients with ATTR-CA compared with patients with AL-CA presented more frequently with shoulder pathologies (p <0.001) and at least 1 orthopedic manifestation (p <0.001). The odds of patients with ATTR-CA and AL-CA aged 60years or older who underwent shoulder arthroplasty was 6.05 times greater (95% confidence interval 4.26 to 8.60) and 1.63 times greater (95% confidence interval 0.67 to 3.94), respectively, compared with age-matched controls. Shoulder pathologies and concomitant orthopedic pathologies are common in patients with ATTR-CA and may help identify patients with CA earlier in their disease progression for earlier intervention and treatment.

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.

361 PATISIRAN EFFICACY ON MYOCARDIAL FUNCTION IN H-ATTR PATIENTS EVALUATED WITH THE USE OF CMR AND SPECKLE TRACKING ECOCARDIOGRAPHY

Abstract Introduction Hereditary transthyretin amyloidosis (h-ATTR) is a complex, systemic infiltrative disease characterized by extracellular deposition of transthyretin in different organs. Infiltrative cardiomyopathy and polyneuropathy represent two of the most common and severe manifestations of this pathology. Patisiran is a double-stranded interfering RNA drug, used to stop expression of TTR in h-ATTR. It is recommended in the treatment of cardiac h-ATTR with polyneuropathy or polyneuropathy alone. Recent studies showed the efficacy of Patisiran in slowing the progression of the disease, improving myocardial deformation indices, biomarkers and functional capacity. Aim We aimed to illustrate the efficacy of Patisiran on myocardial function and to evaluate the role of Speckle Tracking Echocardiography (STE) and Cardiac Magnetic Resonance (CMR) as markers of subclinical cardiac efficacy of Patisiran in two h-ATTR patients (males, with mean age 55 ± 1,4 years old) with infiltrative cardiomyopathy and polyneuropathy who were scheduled to receive this drug. Materials and Methods Before receiving Patisiran (T0) the following tests were performed: cardiovascular physical examination, complete echocardiogram including STE. All these exams were repeated after 6 months or 1 year (T1). CMR was performed at the baseline and three years after. Results The CMR evaluation showed, after the use of Patisiran, a significant reduction of myocardial mass (average reduction -13,29%) and myocardial walls thickness (average septal reduction -13,65%). After 1 year follow up myocardial performance indices were also improved: GLS values (average gain 2,3 pt), and myocardial work values (average increase GWI +311,5, GCW +188,5, GWW -114,5, GWE +5,5 pt) at echocardiography. Conclusion The results of our experience showed, according to evidences suggested by the APOLLO trial, the efficacy of Patisiran, in patients with cardiac h-ATTR and polyneuropathy, in reducing myocardial mass and improving myocardial function. STE and CMR could represent useful tools to study cardiac function in A-TTR patients undergoing Patisiran.

Liver-directed drugs for transthyretin-mediated amyloidosis.

Transthyretin-mediated amyloidosis (ATTR) is a rare, under-recognized, progressively debilitating, fatal disease caused by the aggregation and extracellular deposition of amyloid transthyretin (TTR) fibrils in multiple organs and tissues throughout the body. TTR is predominantly synthesized by the liver and normally circulates as a homotetramer, while misfolded monomers aggregate to form amyloid fibrils. One strategy to treat ATTR amyloidosis is to reduce the amount of TTR produced by the liver using drugs that directly target the TTR mRNA or gene. This narrative review focuses on how TTR gene silencing tools act to reduce TTR production, describing strategies for improved targeted delivery of these agents to hepatocytes where TTR is preferentially expressed. Antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), termed RNA silencers, cause selective degradation of TTR mRNA, while a TTR gene editing tool reduces TTR expression by introducing nonsense mutations into the TTR gene. Two strategies to facilitate tissue-specific delivery of these nucleic acid-based drugs employ endogenous receptors expressed by hepatocytes. Lipid nanoparticles (LNPs) that recruit apolipoprotein E support low-density lipoprotein receptor-mediated uptake of unconjugated siRNA and are now used for CRISPR gene editing tools. Additionally, conjugating N-acetylgalactosamine (GalNAc) moieties to ASOs or siRNAs facilitates receptor-mediated uptake by the asialoglycoprotein receptor. In summary, ATTR is a progressive disease with various clinical manifestations due to TTR aggregation, deposition, and amyloid formation. Receptor-targeted ligands (eg, GalNAc) and nanoparticle encapsulation (eg, LNPs) are technologies to deliver ASOs, siRNAs, and gene editing tools to hepatocytes, the primary location of TTR synthesis.

Abstract 15440: Elevated Serum Transthyretin Concentration Found to be Associated With Increased Survival Rate in Hereditary Transthyretin Cardiomyopathy Patients

Introduction: Transthyretin amyloid cardiomyopathy (ATTR-CM) results from abnormal deposition of misfolded transthyretin (TTR) deposition in the myocardium. Prior studies have shown an association between lower serum concentrations of TTR with increased mortality in patients with wild-type TTR, suggesting that greater deposition of TTR from the blood into surrounding tissues may reflect increased disease severity. Hypothesis: Serum TTR levels are associated with mortality and HF hospitalization in hATTR patients with Val142Ile mutation. Methods: We conducted a retrospective chart review of patients diagnosed with hATTR-CM at Emory University's Cardiac Amyloidosis Clinic between January 2014 and April 2022 (n=65) and evaluated the association of serum TTR concentration with 1 year survival and 1 year HF hospitalization. We stratified patients on two TTR cut-offs: 18 mg/dL, based on a previous study in a wild-type cohort, and 14.9 mg/dL, the median TTR level in this cohort. Kaplan Meier Survival analysis and Cox proportional hazard modeling examined the association between serum TTR, overall survival, and HF hospitalization, adjusted for troponin-I, age, BMI, BNP, GFR and NYHA class as covariates. Results: Increased serum concentrations of TTR were significantly associated with decreased mortality within 1 year of diagnosis in multivariable models. Adjusted models showed a significant difference between the groups at both cut-offs only when the event was death within 1 year of diagnosis (Cutoff 14.9: HR = 14.02, 95% CI 2.4 - 82.5; cutoff 18: HR 367, 95% CI 35.24-3822.57), but no significant difference for the outcome of HF hospitalization at either cutoff point ( Table ). Conclusions: In our cohort of 65 hATTR patients with the Val142Ile mutation, lower TTR levels at the time of diagnosis were significantly associated with death at 1 year of diagnosis. TTR levels were not significantly associated with HF hospitalization within 1 year of diagnosis.

Development of a Highly Potent Transthyretin Amyloidogenesis Inhibitor: Design, Synthesis, and Evaluation.

Transthyretin amyloidosis (ATTR) is a group of fatal diseases described by the misfolding and amyloid deposition of transthyretin (TTR). Discovering small molecules that bind and stabilize the TTR tetramer, preventing its dissociation and subsequent aggregation, is a therapeutic strategy for these pathologies. Departing from the crystal structure of TTR in complex with tolcapone, a potent binder in clinical trials for ATTR, we combined rational design and molecular dynamics (MD) simulations to generate a series of novel halogenated kinetic stabilizers. Among them, M-23 displays one of the highest affinities for TTR described so far. The TTR/M-23 crystal structure confirmed the formation of unprecedented protein-ligand contacts, as predicted by MD simulations, leading to an enhanced tetramer stability both in vitro and in whole serum. We demonstrate that MD-assisted design of TTR ligands constitutes a new avenue for discovering molecules that, like M-23, hold the potential to become highly potent drugs to treat ATTR.

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.

SUCCESSFUL MANAGEMENT OF REFRACTORY CONSTIPATION USING KAMPO MEDICINE MASHININGAN IN A PATIENT WITH WILD-TYPE ATTR CARDIAC AMYLOIDOSIS

TYPE: Case Report TOPIC: Cardiovascular Disease INTRODUCTION: A wild-type ATTR amyloidosis is a systemic disease with multi-organ dysfunction, involving heart, kidney, skin, and gastrointestinal tract, due to deposition of wild-type transthyretin in each organ. CASE PRESENTATION: We had a 76-year-old man diagnosed with wild-type ATTR cardiac amyloidosis, whose heart failure symptom improved by anti-heart failure medications but constipation refractory to multiple conventional medications persisted. Following the conversion from lubiprostone to Kampo medicine mashiningan, his average days per one evacuation decreased from around 7.0 days down to 1.6 days. DISCUSSION: Amyloid-related gastrointestinal comorbidities are often refractory to the conventional medications. Mashiningan might increase the proportion of soft feces via increasing intestinal fluid secretion through cystic fibrosis transmembrane conductance regulator chloride channel activation. CONCLUSIONS: Mashininigan might be alternative option to improve refractory constipation in patients with cardiac amyloidosis. DISCLOSURE: Nothing to declare. KEYWORD: heart failure

Progressive Multiple Mononeuropathy in a Patient With Familial Transthyretin Amyloidosis After Liver Transplantation

Valine 122 isoleucine (V122I) is the most common mutation associated with familial transthyretin-related amyloidosis (fATTR) in the metropolitan United States. V122I-related fATTR usually presents with cardiomyopathy. When polyneuropathy is encountered, it is usually mild, distal, and axonal in nature. Although liver transplantation improves survival for fATTR neuropathy patients, neuropathy may progress post liver transplantation because of the deposition of wild-type transthyretin. We report a patient with homozygous V122I mutation who presented with asymmetrical, upper limb predominant neuropathy rather early in his disease course, which progressed for a period of 5 years after liver transplantation before stabilization with the initiation of patisiran.