RNA Targeting and Gene Editing Strategies for Transthyretin Amyloidosis

Transthyretin (TTR) is a tetrameric protein synthesized primarily by the liver. TTR can misfold into pathogenic ATTR amyloid fibrils that deposit in the nerves and heart, causing a progressive and debilitating polyneuropathy (PN) and life-threatening cardiomyopathy (CM). Therapeutic strategies, which are aimed at reducing ongoing ATTR amyloid fibrillogenesis, include stabilization of the circulating TTR tetramer or reduction of TTR synthesis. Small interfering RNA (siRNA) or antisense oligonucleotide (ASO) drugs are highly effective at disrupting the complementary mRNA and inhibiting TTR synthesis. Since their development, patisiran (siRNA), vutrisiran (siRNA) and inotersen (ASO) have all been licensed for treatment of ATTR-PN, and early data suggest these drugs may have efficacy in treating ATTR-CM. An ongoing phase 3 clinical trial will evaluate the efficacy of eplontersen (ASO) in the treatment of both ATTR-PN and ATTR-CM, and a recent phase 1 trial demonstrated the safety of novel in vivo CRISPR-Cas9 gene-editing therapy in patients with ATTR amyloidosis. Recent results from trials of gene silencer and gene-editing therapies suggest these novel therapeutic agents have the potential to substantially alter the landscape of treatment for ATTR amyloidosis. Their success has already changed the perception of ATTR amyloidosis from a universally progressive and fatal disease to one that is treatable through availability of highly specific and effective disease-modifying therapies. However, important questions remain including long-term safety of these drugs, potential for off-target gene editing, and how best to monitor the cardiac response to treatment.Kindly check and confirm the processed running title.This is correct

Imaging-Guided Treatment for Cardiac Amyloidosis

PURPOSE OF REVIEW: This review will explore the role of cardiac imaging in guiding treatment in the two most commonly encountered subtypes of cardiac amyloidosis (immunoglobulin light-chain amyloidosis [AL] and transthyretin amyloidosis [ATTR]). RECENT FINDINGS: Advances in multi-parametric cardiac imaging involving a combination of bone scintigraphy, echocardiography and cardiac magnetic resonance imaging have resulted in earlier diagnosis and initiation of treatment, while the evolution of techniques such as longitudinal strain and extracellular volume quantification allow clinicians to track individuals' response to treatment. Imaging developments have led to a deeper understanding of the disease process and treatment mechanisms, which in combination result in improved patient outcomes. The rapidly expanding treatment regimens for cardiac amyloidosis have led to an even greater reliance on cardiac imaging to help establish an accurate diagnosis, monitor treatment response and aid the adjustment of treatment strategies accordingly

Rare Forms of Cardiac Amyloidosis: Diagnostic Clues and Phenotype in Apo AI and AIV Amyloidosis

BACKGROUND: Apo AI amyloidosis (AApoAI) and Apo AIV amyloidosis (AApoAIV) are rare but increasingly recognized causes of cardiac amyloidosis (CA). We sought to define the cardiac phenotype in AApoAI and AApoAIV using multimodality imaging. METHODS: We identified all patients with AApoAI and AApoAIV assessed at our center between 2000 and 2021, and 2 cohorts of patients with immunoglobulin light-chain amyloidosis (AL) and transthyretin amyloidosis matched for age, sex, and cardiac involvement. RESULTS: Forty-five patients had AApoAI, 13 (29%) of whom had cardiac involvement, 32 (71%) renal involvement, 28 (62%) splenic involvement, 27 (60%) hepatic involvement, and 7 (16%) laryngeal involvement. AApoAI-CA commonly presented with heart failure (n=8, 62%) or dysphonia (n=7, 54%). The Arg173Pro variant universally caused cardiac and laryngeal involvement (n=7, 100%). AApoAI-CA was associated with right-sided involvement, with a thicker right ventricular free wall (8.6±1.9 versus 6.3±1.3 mm versus 7.7±1.2 mm, P=0.004), greater incidence of tricuspid stenosis (4 [31%] versus 0 [0%] versus 0 [0%], P=0.012) and tricuspid regurgitation (6 [46%] versus 1 [8%] versus 2 [15%], P=0.048) than AL-CA and transthyretin CA. Twenty-one patients had AApoAIV, and cardiac involvement was more common than in AApoAI (15 [71%] versus 13 [29%], P=0.001). AApoAIV-CA most commonly presented with heart failure (n=12, 80%), and a lower median estimated glomerular filtration rate than AL-CA and transthyretin CA (36 mL/[min·1.73 m²] versus 65 mL/[min·1.73 m²] versus 63 mL/[min·1.73 m²], P172 and >30 months, respectively), and a lower risk of mortality than matched patients with AL-amyloidosis (AL versus AApoAI: hazard ratio, 4.54 [95% CI, 2.02-10.14]; P<0.001; AL versus AApoAIV: hazard ratio, 3.07 [95% CI, 1.27-7.44]; P=0.013). CONCLUSIONS: Dysphonia, multisystem involvement, or right-sided cardiac disease should raise suspicion of AApoAI-CA. AApoAIV-CA presents most commonly with heart failure and always displays classical CA imaging features, mimicking common forms of CA. Both AApoAI and AApoAIV are associated with a good prognosis and a lower risk of mortality than matched patients with AL-amyloidosis

External electrical and pharmacological cardioversion for atrial fibrillation, atrial flutter or atrial tachycardias:a network meta-analysis

BackgroundAtrial fibrillation (AF) is the most frequent sustained arrhythmia. Cardioversion is a rhythm control strategy torestore normal/sinus rhythm, and can be achieved through drugs (pharmacological) or a synchronized electricshock (electrical cardioversion).ObjectivesTo assess the efficacy and safety of pharmacological and electrical cardioversion for AF.Search methodsWe searched CENTRAL, MEDLINE, Embase, Conference Proceedings Citation Index-Science (CPCI-S) andthree trials registers (ClinicalTrials.gov, WHO ICTRP and ISRCTN) on 14 February 2023.Selection criteriaWe included randomised controlled trials (RCTs) at individual patient level. Patient populations were aged ≥18years with AF of any type and duration, atrial flutter or other sustained related atrial arrhythmias, not occurring asa result of reversible causes.Data collection and analysisWe used standard Cochrane methodology to collect data and performed a network meta-analysis using thestandard frequentist graph-theoretical approach using the netmeta package in R. We used GRADE to assess thequality of the evidence which we presented in in our summary of findings with a judgement on certainty. Wecalculated differences using risk ratios (RR) and 95% confidence intervals (CI) as well as ranking treatmentsusing a P-score. We assessed clinical and statistical heterogeneity and split the networks for the primaryoutcome and acute procedural success due to concerns about violating the transitivity assumption.Main resultsWe included 112 RCTs (139 records), from which we pooled data from 15,968 patients. Average age was 47 to72 years and proportion of male patients was 38%-92%.79 trials were considered high risk of bias for at least one domain, 32 had no high risk of bias domains, but hadat least one domain classified as uncertain risk, and one study was considered low risk for all domains.For paroxysmal AF (35 trials), when compared to Placebo, AA/AP BTE incremental cardioversion (RR: 2.42;95%CI 1.65 to 3.56), quinidine (RR: 2.23; 95%CI 1.49 to 3.34), ibutilide (RR: 2.00; 95%CI 1.28 to 3.12),propafenone (RR: 1.98; 95%CI 1.67 to 2.34), amiodarone (RR: 1.69; 95%CI 1.42 to 2.02), sotalol (RR: 1.58;95%CI 1.08 to 2.31) and procainamide (RR: 1.49; 95%CI 1.13 to 1.97) likely result in a large increase inmaintenance of sinus rhythm until hospital discharge or end of study follow-up (certainty of evidence: moderate).The effect size was larger for AA/AP incremental and was progressively smaller for the subsequent interventions.Despite low certainty of evidence Antazoline may result in a large increase (RR: 28.60; 95%CI 1.77 to 461.30) inthis outcome. Similarly, low certainty evidence suggests a large increase on this outcome for flecainide (RR: 2.17;95%CI 1.68 to 2.79), vernakalant (RR: 2.13; 95%CI 1.52 to 2.99), and magnesium (RR: 1.73; 95%CI 0.79 to 3.79)on this outcome.For persistent AF (26 trials), one network was created for electrical cardioversion and showed that whencompared to AP BTE incremental energy with patches, AP BTE maximum energy with patches (RR 1.35, 95%CI1.17 to 1.55) likely results in large increase and Active compression AP BTE incremental energy with patches(RR: 1.14, 95%CI 1.00 to 1.131) likely results in an increase in maintenance of sinus rhythm at hospital dischargeor end of study follow-up (certainty of evidence: high). Use of AP BTE incremental with paddles (RR: 1.03, 95%CI0.98 to 1.09; certainty of evidence: low) may lead to a little increase, and AP MDS Incremental paddles (RR: 0.95,95%CI 0.86 to 1.05; certainty of evidence: low) may lead to a little decrease in efficacy. On the other hand, APMDS incremental energy using patches (RR: 0.78, 95%CI 0.70 to 0.87), AA RBW incremental energy withpatches (RR: 0.76, 95%CI 0.66 to 0.88), AP RBW incremental energy with patches (RR: 0.76, 95%CI 0.68 to0.86), AA MDS incremental energy with patches (RR: 0.76, 95%CI 0.67 to 0.86) and AA MDS incremental energywith paddles (RR: 0.68, 95%CI 0.53 to 0.83) probably result in a decrease on this outcome when compared to APBTE incremental energy with patches (certainty of evidence: moderate). The network for pharmacologicalcardioversion showed that Bepridil (RR: 2.29, 95%CI 1.26 to 4.17) and Quindine (RR: 1.53, (95%CI 1.01 to 2.32)probably result in large increase in maintenance of sinus rhythm at hospital discharge or end of study follow-upwhen compared to amiodarone (certainty of evidence: moderate). Dofetilide (RR: 0.79, 95%CI 0.56 to 1.44),Sotalol (RR: 0.89, 95%CI 0.67 to 1.18), Propafenone (RR: 0.79, 95%CI 0.50 to 1.25) and Pilsicainide (RR: 0.39,95%CI 0.02 to 7.01) may result in a reduction of this outcome when compared to amiodarone, but certainty ofevidence is lowFor atrial flutter (14 trials) a network could be created only for antiarrhythmic drugs. Using Placebo as thecommon comparator, ibutilide (RR: 21.45, 95%CI 4.41 to 104.37), propafenone (RR: 7.15, 95%CI 1.27 to 40.10),dofetilide (RR: 6.43, 95%CI 1.38 to 29.91), and sotalol (RR: 6.39, 95%CI 1.03 to 39.78) probably result in a largeincrease in maintenance of sinus rhythm at hospital discharge or end of study follow-up (certainty of evidence:moderate), and procainamide (RR: 4.29, 95%CI 0.63 to 29.03), flecainide (RR 3.57, 95%CI 0.24 to 52.30) andvernakalant (RR: 1.18, 95%CI 0.05 to 27.37) may result in a large increase of maintenance of sinus rhythm athospital discharge or end of study follow-up at (certainty of evidence: low) All tested electrical cardioversionstrategies for atrial flutter had very high efficacy (97.9% to 100%).Mortality (14 deaths) and Stroke or systemic embolism (3 events) at 30 days was extremely low.Data on quality of life were scarce and of uncertain clinical significance. No information was available regardingheart failure readmissions. Data on duration of hospitalization was scarce, low quality, &amp; could not be pooled.Authors' conclusionsDespite the low quality of evidence, this systematic review provides important information on electrical andpharmacological strategies to help patients and physicians deal with AF and atrial flutter.Assessing the patient comorbidity profile, antiarrhythmic drug onset of action &amp; side effect profile vs. need for aphysician with experience in sedation, or anaesthetics support, for electrical cardioversion are key aspects whenchoosing the cardioversion method

Prognostic Value of a 6-Minute Walk Test in Patients With Transthyretin Cardiac Amyloidosis

Background The 6-minute walk test (6MWT) represents a comprehensive functional assessment that is commonly used in patients with heart failure; however, data are lacking in patients with transthyretin cardiac amyloidosis (ATTR-CA). Objectives This study aimed to assess the prognostic importance of the 6MWT in patients with ATTR-CA.Methods A retrospective analysis of patients diagnosed with ATTR-CA at the National Amyloidosis Centre who underwent a baseline 6MWT between 2011 and 2023 identified 2,141 patients, of whom 1,118 had follow-up at 1 year.Results The median baseline 6MWT distance was 347 m (Q1-Q3: 250-428 m) and analysis by quartiles demonstrated an increased death rate with each distance reduction (deaths per 100 person-years: 6.3 vs 9.2 vs 13.6 vs 19.0; log-rank P &lt; 0.001). A 6MWT distance of 35 m) and relative worsening (reduction of &gt;5%) of 6MWT at 1 year was associated with an increased risk of mortality (HR: 1.80; 95% CI: 1.51-2.15; P &lt; 0.001 and HR: 1.89; 95% CI: 1.59-2.24; P &lt; 0.001, respectively), which was similar across the aforementioned subgroups. When combined with established measures of disease progression (N-terminal pro–B-type natriuretic peptide progression and outpatient diuretic intensification), each incremental increase in progression markers was associated with an increased death rate (deaths per 100 person-years: 7.6 vs 13.9 vs 22.4 vs 32.9; log-rank P &lt; 0.001). Conclusions The baseline 6MWT distance can refine risk stratification beyond traditional prognosticators. A worsening 6MWT distance can stratify disease progression and, when combined with established markers, identifies patients at the highest risk of mortality

Multi-Imaging Characterization of Cardiac Phenotype in Different Types of Amyloidosis

BACKGROUND: Bone scintigraphy is extremely valuable when assessing patients with suspected cardiac amyloidosis (CA), but the clinical significance and associated phenotype of different degrees of cardiac uptake across different types is yet to be defined. OBJECTIVES: This study sought to define the phenotypes of patients with varying degrees of cardiac uptake on bone scintigraphy, across multiple types of systemic amyloidosis, using extensive characterization comprising biomarkers as well as echocardiographic and cardiac magnetic resonance (CMR) imaging. METHODS: A total of 296 patients (117 with immunoglobulin light-chain amyloidosis [AL], 165 with transthyretin (TTR) amyloidosis [ATTR], 7 with apolipoprotein AI amyloidosis [AApoAI], and 7 with apolipoprotein AIV amyloidosis [AApoAIV]) underwent deep characterization of their cardiac phenotype. RESULTS: AL patients with grade 0 myocardial radiotracer uptake spanned the spectrum of CMR findings from no CA to characteristic CA, whereas AL patients with grades 1 to 3 always produced characteristic CMR features. In ATTR, the CA burden strongly correlated with myocardial tracer uptake, except in Ser77Tyr. AApoAI presented with grade 0 or 1 and disproportionate right-sided involvement. AApoAIV always presented with grade 0 and characteristic CA. AL grade 1 patients (n = 48; 100%) had characteristic CA, whereas only ATTR grade 1 patients with Ser77Tyr had characteristic CA on CMR (n = 5; 11.4%). After exclusion of Ser77Tyr, AApoAI, and AApoAIV, CMR showing characteristic CA or an extracellular volume of >0.40 in patients with grade 0 to 1 cardiac uptake had a sensitivity and specificity of 100% for AL. CONCLUSIONS: There is a wide variation in cardiac phenotype between different amyloidosis types across different degrees of cardiac uptake. The combination of CMR and bone scintigraphy can help to define the diagnostic differentials and the clinical phenotype in each individual patient

Prevalence, Characteristics and Outcomes of Older Patients with Hereditary versus Wild-Type Transthyretin Amyloid Cardiomyopathy

BACKGROUND: Transthyretin amyloid cardiomyopathy (ATTR-CM) is often assumed to be associated with wild-type TTR genotype (ATTRwt) in elderly patients (aged >70), some of whom are not offered genetic testing. We sought to estimate the prevalence, clinical characteristics and prognostic implications of TTR variants among elderly patients diagnosed with ATTR-CM. METHODS: Data from consecutive patients over 70 years of age diagnosed with ATTR-CM at the UK National Amyloidosis Centre between January 2010 and August 2022 were retrospectively evaluated. All patients underwent clinical evaluation, biochemical tests, echocardiography and TTR genotyping. The study outcome was all-cause mortality. RESULTS: The study population consisted of 2029 patients with ATTR-CM (median age 79 years at diagnosis, 13.2% females, 80.4% Caucasian). Variant ATTR-CM (ATTRv-CM) was diagnosed in 20.7% (n=421) of the study population of whom 329 (76.3%) carried V122I, 49 (11.4%) T60A, 18 (4.2%) V30M and 35 (8.1%) other pathogenic TTR variants. During a median (range) follow up of 29 (12-48) months, ATTRv-CM was associated with increased all-cause mortality compared to ATTRwt-CM, with the poorest survival observed in V122I-associated ATTRv-CM (p<0.001). Univariable and multivariable logistic regression analyses in those with ATTR-CM showed younger age at diagnosis (odds ratio [OR] 0.85 per year, p<0.001), female sex (OR 2.73, p<0.001), Afro-Caribbean ethnicity (OR 65.5, p<0.001), atrial fibrillation (OR 0.65, p=0.015), ischemic heart disease (OR 0.54, p=0.007), peripheral polyneuropathy (OR 5.70, p<0.001) and orthostatic hypotension (OR 6.29, p<0.001) to be independently associated with ATTRv-CM. CONCLUSION: Up to 20.7% of elderly patients with ATTR-CM have a pathogenic TTR variant. These findings support routine sequencing of the TTR gene in all patients with ATTR-CM regardless of age. This article is protected by copyright. All rights reserved

Tracking Treatment Response in Cardiac Light-Chain Amyloidosis With Native T1 Mapping

IMPORTANCE: Cardiac magnetic resonance (CMR) imaging-derived extracellular volume (ECV) mapping, generated from precontrast and postcontrast T1, accurately determines treatment response in cardiac light-chain amyloidosis. Native T1 mapping, which can be derived without the need for contrast, has demonstrated accuracy in diagnosis and prognostication, but it is unclear whether serial native T1 measurements could also track the cardiac treatment response. OBJECTIVE: To assess whether native T1 mapping can measure the cardiac treatment response and the association between changes in native T1 and prognosis. DESIGN, SETTING, AND PARTICIPANTS: This single-center cohort study evaluated patients diagnosed with cardiac light-chain amyloidosis (January 2016 to December 2020) who underwent CMR scans at diagnosis and a repeat scan following chemotherapy. Analysis took place between January 2016 and October 2022. MAIN OUTCOMES AND MEASURES: Comparison of biomarkers and cardiac imaging parameters between patients with a reduced, stable, or increased native T1 and association between changes in native T1 and mortality. RESULTS: The study comprised 221 patients (mean [SD] age, 64.7 [10.6] years; 130 male [59%]). At 6 months, 183 patients (mean [SD] age, 64.8 [10.5] years; 110 male [60%]) underwent repeat CMR imaging. Reduced native T1 of 50 milliseconds or more occurred in 8 patients (4%), all of whom had a good hematological response; by contrast, an increased native T1 of 50 milliseconds or more occurred in 42 patients (23%), most of whom had a poor hematological response (27 [68%]). At 12 months, 160 patients (mean [SD] age, 63.8 [11.1] years; 94 male [59%]) had a repeat CMR scan. A reduced native T1 occurred in 24 patients (15%), all of whom had a good hematological response, and was associated with a reduction in N-terminal pro-brain natriuretic peptide (median [IQR], 2638 [913-5767] vs 423 [128-1777] ng/L; P < .001), maximal wall thickness (mean [SD], 14.8 [3.6] vs 13.6 [3.9] mm; P = .009), and E/e' (mean [SD], 14.9 [6.8] vs 12.0 [4.0]; P = .007), improved longitudinal strain (mean [SD], -14.8% [4.0%] vs -16.7% [4.0%]; P = .004), and reduction in both myocardial T2 (mean [SD], 52.3 [2.9] vs 49.4 [2.0] milliseconds; P < .001) and ECV (mean [SD], 0.47 [0.07] vs 0.42 [0.08]; P < .001). At 12 months, an increased native T1 occurred in 24 patients (15%), most of whom had a poor hematological response (17 [71%]), and was associated with an increased N-terminal pro-brain natriuretic peptide (median [IQR], 1622 [554-5487] vs 3150 [1161-8745] ng/L; P = .007), reduced left ventricular ejection fraction (mean [SD], 65.8% [11.4%] vs 61.5% [12.4%]; P = .009), and an increase in both myocardial T2 (mean [SD], 52.5 [2.7] vs 55.3 [4.2] milliseconds; P < .001) and ECV (mean [SD], 0.48 [0.09] vs 0.56 [0.09]; P < .001). Change in myocardial native T1 at 6 months was independently associated with mortality (hazard ratio, 2.41 [95% CI, 1.36-4.27]; P = .003). CONCLUSIONS AND RELEVANCE: Changes in native T1 in response to treatment, reflecting a composite of changes in T2 and ECV, are associated with in changes in traditional markers of cardiac response and associated with mortality. However, as a single-center study, these results require external validation in a larger cohort