First report of the clinical characteristics and outcomes of cardiac amyloidosis in Saudi Arabia.

AIMS: Cardiac amyloidosis (CA) is a potentially fatal multisystemic disease that remains significantly underdiagnosed, particularly in the Middle East. This study aims to evaluate the prevalence and clinical characteristics of CA in a high-risk population at a tertiary centre in Saudi Arabia. METHODS: This cross-sectional, retrospective, single-centre study was conducted at a tertiary hospital in Riyadh, Saudi Arabia. We reviewed the medical records of heart failure patients seen between August 2018 and July 2022 who exhibited red flags for CA and subsequently underwent CA screening. Red flags that prompted the workup included at least two of the following factors: the presence of unilateral or bilateral carpal tunnel syndrome, a family history of transthyretin amyloid (ATTR) amyloidosis and specific electrocardiographic features (relative/absolute low QRS voltage, pseudoinfarct pattern and atrioventricular/interventricular conduction abnormalities). Echocardiographic red flags included mainly increased wall thickness (≥12 mm), significant diastolic dysfunction, reduced left ventricular (LV) longitudinal function, right ventricular (RV) dysfunction and elevated right atrial (RA)/pulmonary artery (PA) pressure. Cardiac magnetic resonance (CMR) red flags included aspects similar to those in an echocardiogram as well as a subendocardial or transmural late gadolinium enhancement (LGE) pattern. These patients were assessed for CA through technetium-99m pyrophosphate ([99mTc]Tc-PYP) bone scintigraphy, serum and urine protein electrophoresis with immunofixation and a serum-free light chain assay. RESULTS: A total of 177 patients were screened, of which 21.0 (11.9%) patients were diagnosed with transthyretin amyloid CA (ATTR-CA) and 13 (7.3%) patients were diagnosed with light chain CA (AL-CA). Compared with patients with negative/equivocal [99mTc]Tc-PYP scans (grades 0-1), patients with positive [99mTc]Tc-PYP scans (grades 2-3) were older (78.0 vs. 68.0 years, P < 0.001), had higher levels of troponin (P = 0.003) and N-terminal pro-brain natriuretic peptide (NT-proBNP) (P < 0.001), had a higher LV mass index (P < 0.001), displayed a more depressed global longitudinal strain (GLS) (P < 0.001) with a greater prevalence of a relative apical sparing pattern (P < 0.001) and demonstrated a higher incidence of first-degree atrioventricular block (P = 0.008) and low voltage patterns on electrocardiography (P < 0.001). Patients with ATTR-CA and AL-CA were more likely to have a subendocardial or transmural LGE pattern on CMR (P < 0.001) and had a significantly lower overall survival (P < 0.001) when compared with other heart failure aetiologies. CONCLUSIONS: This is the first study to describe the clinical characteristics and outcomes of CA in the Middle East and Saudi Arabia. The prevalence of CA among screened heart failure patients here aligns with major international studies, suggesting significant underdiagnosis in the region. Therefore, larger multicentric studies and regional screening programmes are urgently needed to accurately characterize the epidemiology and outcomes of CA in the Middle East.

Symptoms of Hereditary Transthyretin Amyloidosis: The Patient and Physician Perspective.

This article has been co-authored by a patient living with hereditary transthyretin (ATTRv) amyloidosis and a neurologist. This rare, progressive disease is associated with impairment of multiple organ systems, including the nerves, heart, and the gastrointestinal tract, forcing patients to live with and adapt to a range of debilitating symptoms. Here, the patient and physician discuss how the symptoms of ATTRv amyloidosis profoundly impact day to day life, the difficulties with identifying the disease, and how this effects the diagnosis experience. In recent years, significant advancements have been made in the treatment and management of ATTRv amyloidosis. However, the authors highlight the urgency of increasing awareness of the disease among the wider medical community, as well as in patients who notice the symptoms, to ensure that earlier diagnosis and appropriate treatment are achieved.

Assessment of transthyretin instability in patients with wild-type transthyretin amyloid cardiomyopathy.

The pathophysiology of variant transthyretin (TTR) amyloidosis (ATTRv) is associated with destabilizing mutations in the TTR tetramer. However, why TTR with a wild-type genetic sequence misfolds and aggregates in wild-type transthyretin amyloidosis (ATTRwt) is unknown. Here, we evaluate kinetic TTR stability with a newly developed ELISA system in combination with urea-induced protein denaturation. Compared with that in control patients, endogenous TTR in patients with wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) exhibited thermodynamic instability, indicating that circulating TTR instability may be associated with the pathogenesis of ATTRwt as well as ATTRv. Our findings provide new insight into the underlying mechanisms of ATTRwt.

Cardiac amyloidosis: A diagnostic challenge.

Cardiac amyloidosis is indeed a condition characterized by the deposition of amyloid proteins in the myocardium, leading to thickening and stiffening of the heart muscle. These abnormal protein deposits can interfere with the heart's normal functioning and may pose diagnostic challenges due to its varied clinical presentation and resemblance to other heart condition. Here, we present a case of 55-year-old female patient of uncontrolled hypertensions for 15 years. About 15 years ago, she presented with chest pain and was diagnosed with cardiomyopathy (CM) characterized by low left ventricle (LV) function of unknown cause. Despite being on antihypertensive treatment, the patient continued to experience chest heaviness with persistent elevate blood pressure. An echocardiogram revealed increased LV septal wall thickness, valvular thickening, and biatrial dilation. Subsequently, cardiac magnetic resonance imaging (CMR) was performed, which revealed left atrium enlargement and asymmetrical myocardial wall thickening, particularly at the septum. White blood axial image revealed thickened inter atrial septum, while late gadolinium enhancement (LGE) magnetic resonance (LGE MR) images showed patchy LGE at the base relative to the apex of the myocardium, highlighting the base-to-apex gradient, subendocardial pattern enhancement at apical lateral wall, and transmural pattern enhancement of the mid anteroseptal and inferoseptal wall. Additionally, a short axis time to invert T1 scout image of left ventricle displayed an abnormal nulling pattern initially in the myocardium, followed by the blood pool, and finally the spleen. These findings collectively led to the diagnosis of cardiac amyloidosis.

The Mayo ATTR-CM score versus other diagnostic scores and cardiac biomarkers in patients with suspected cardiac amyloidosis.

AIMS: Several scores were developed to help the diagnosis of cardiac amyloidosis (CA). The most recent one, being the Mayo transthyretin amyloidosis cardiomyopathy (ATTR-CM) score, was not externally validated. We compared the diagnostic performance of the ATTR-CM score with previous tools (increased wall thickness [IWT] score, AMYLoidosis Index [AMYLI] score, and cardiac biomarkers) in a cohort of patients evaluated for a suspicion of CA. METHODS AND RESULTS: We analysed 362 consecutive patients referred to a third-level centre for suspected CA. Overall, 132 (36%) had transthyretin CA (ATTR-CA), and 91 (25%) immunoglobulin light chain CA (AL-CA); CA was excluded in 139 (38%). ATTR-CM score had a good diagnostic performance to distinguish ATTR-CA from AL-CA or no CA, with an area under the curve (AUC) of 0.795 (95% confidence interval [CI] 0.747-0.842, p < 0.001), and ATTR-CA from no CA (AUC 0.822, 95% CI 0.774-0.871, p < 0.001). Results were consistent in both patients with preserved (AUC 0.787, 95% CI 0.726-0.848, p < 0.001), and reduced or mildly reduced ejection fraction (AUC 0.790, 95% CI 0.709-0.871, p < 0.001). The ATTR-CM score showed a better discrimination compared to IWT and AMYLI score to distinguish ATTR-CA from AL-CA or no CA (p = 0.002), but not to distinguish ATTR-CA from no CA (p = 0.270). Diagnostic accuracy was significantly higher for the ATTR-CM score as compared to the rule-in cut-off of high-sensitivity troponin T. CONCLUSION: The Mayo ATTR-CM score has a good performance in identifying patients with ATTR-CA, with also better discrimination power when compared to other scores and biomarkers.

The effect of long-term tafamidis treatment on quality of life in people with transthyretin amyloid cardiomyopathy (ATTR-CM): A plain language summary.

WHAT IS THIS SUMMARY ABOUT?: This summary explains some results of a study called ATTR-ACT and its ongoing long-term extension study that were published in the European Journal of Heart Failure. The purpose of ATTR-ACT was to find out if a drug called tafamidis is an effective treatment for people with a heart condition called transthyretin amyloid cardiomyopathy (ATTR-CM). People took tafamidis or placebo for up to 2.5 years in ATTR-ACT (the initial study). A placebo looks like the study medicine but does not contain any active ingredients. After people completed the initial study, they could take part in the extension study. An extension study allows people to continue receiving treatment after the original clinical study ends and helps researchers understand how well a treatment works over a longer time period. This extension study allows people to receive tafamidis for up to an additional 5 years. People who took placebo in the initial study now receive tafamidis. People who took tafamidis in the initial study continue tafamidis treatment. Researchers looked at changes in peoples' ability to enjoy life ('quality of life') and heart failure symptoms since they started ATTR-ACT. Results are available for the first 2.5 years of the extension study. WHAT ARE THE KEY TAKEAWAYS?: During the initial study, there was less worsening of quality of life and heart failure symptoms in people who took tafamidis compared to people who took placebo. In the extension study, quality of life and heart failure symptoms were maintained or nearly maintained in people who took tafamidis in the initial study. In people who started tafamidis in the extension study, quality of life and heart failure symptoms continued to worsen, but the worsening slowed down. WHAT WERE THE MAIN CONCLUSIONS REPORTED BY THE RESEARCHERS?: Tafamidis slows the worsening of quality of life and heart failure symptoms in people with ATTR-CM. People with ATTR-CM should start treatment early to receive the most benefit.Clinical Trial Registration: NCT01994889 (ATTR-ACT) (ClinicalTrials.gov).

Rare Variant of Hereditary Amyloid Transthyretin Cardiomyopathy Secondary to Ser97Tyr Mutation.

Hereditary transthyretin amyloidosis (hATTR) is an autosomal dominant, adult-onset disease that stems from point mutations in the TTR gene encoding the protein transthyretin. The disease is progressive and life-threatening and is associated with amyloid deposits in multiple organs including the heart, kidney, skin, eyes, nervous system, and gastrointestinal tract. Genotypic and phenotypic heterogeneity is a characteristic hallmark of hereditary transthyretin amyloidosis. Herein, we present a rare variant of hATTR cardiomyopathy secondary to Ser97Tyr mutation, having been documented only in a handful of families previously. This case serves as a valuable opportunity to elucidate the clinico-pathogenesis of this disease, highlight the aggressive nature of this genetic mutation (c.290C>A; p.Ser97Tyr), and document the response to the latest advances in treatment currently available.

T2-relaxometry in a large cohort of hereditary transthyretin amyloidosis with polyneuropathy.

BACKGROUND: Previously, T2-relaxation time (T2app) and proton spin density (ρ) detected nerve injury in a small group of ATTRv amyloidosis. Here, we aim to quantify peripheral nerve impairment in a large cohort of symptomatic and asymptomatic ATTRv amyloidosis and correlate T2-relaxometry markers with clinical parameters and nerve conduction studies (NCS). METHODS: Eighty participants with pathologic variants of the transthyretin gene (TTRv) and 40 controls prospectively underwent magnetic resonance neurography. T2-relaxometry was performed, allowing to calculate tibial ρ, T2app and cross-sectional-area (CSA). Detailed clinical examinations and NCS of tibial and peroneal nerves were performed. RESULTS: Forty participants were classified as asymptomatic TTRv-carriers, 40 as symptomatic patients with polyneuropathy. ρ, T2app and CSA were significantly higher in symptomatic ATTRv amyloidosis (484.2 ± 14.8 a.u.; 70.6 ± 1.8 ms; 25.7 ± 0.9 mm2) versus TTRv-carriers (413.1 ± 9.4 a.u., p < 0.0001; 62.3 ± 1.3 ms, p = 0.0002; 19.0 ± 0.8 mm2, p < 0.0001) and versus controls (362.6 ± 7.5 a.u., p < 0.0001; 59.5 ± 1.0 ms, p < 0.0001; 15.4 ± 0.5 mm2, p < 0.0001). Only ρ and CSA differentiated TTRv-carriers from controls. ρ and CSA correlated with NCS in TTRv-carriers, while T2app correlated with NCS in symptomatic ATTRv amyloidosis. Both ρ and T2app correlated with clinical score. CONCLUSION: ρ and CSA can detect early nerve injury and correlate with electrophysiology in asymptomatic TTRv-carriers. T2app increases only in symptomatic ATTRv amyloidosis in whom it correlates with clinical scores and electrophysiology. Our results suggest that T2-relaxometry can provide biomarkers for disease- and therapy-monitoring in the future.

Experience with tafamidis in peritoneal dialysis for a patient diagnosed with transthyretin cardiac amyloidosis.

Cardiac amyloidosis is a cardiomyopathy resulting from the extracellular deposition of proteins such as transthyretin (TTR). We present the case of a 72-year-old male with hereditary cardiac amyloidosis. After confirming the diagnosis, tafamidis, a TTR stabilizer, was administered. Remarkably, tafamidis, when coupled with peritoneal dialysis for chronic kidney disease, maintained stability in both cardiac and renal functions. Previous studies have demonstrated the efficacy of tafamidis in reducing all-cause mortality and cardiovascular hospitalizations, although its use in severe renal failure lacks specific evaluation. This case suggests a potential application of tafamidis in moderate-severe kidney disease, emphasizing the need for further research in this population.

Mechanisms of damage and therapies for cardiac amyloidosis: a role for inflammation?

The term cardiac amyloidosis (CA) refers to the accumulation of extracellular amyloid deposits in the heart because of different conditions often affecting multiple organs including brain, kidney and liver. Notably, cardiac involvement significantly impacts prognosis of amyloidosis, with cardiac biomarkers playing a pivotal role in prognostic stratification. Therapeutic management poses a challenge due to limited response to conventional heart failure therapies, necessitating targeted approaches aimed at preventing, halting or reversing amyloid deposition. Mechanisms underlying organ damage in CA are multifactorial, involving proteotoxicity, oxidative stress, and mechanical interference. While the role of inflammation in CA remains incompletely understood, emerging evidence suggests its potential contribution to disease progression as well as its utility as a therapeutic target. This review reports on the cardiac involvement in systemic amyloidosis, its prognostic role and how to assess it. Current and emerging therapies will be critically discussed underscoring the need for further efforts aiming at elucidating CA pathophysiology. The emerging evidence suggesting the contribution of inflammation to disease progression and its prognostic role will also be reviewed possibly offering insights into novel therapeutic avenues for CA.

Transthyretin amyloid cardiomyopathy: Literature review and red-flag symptom clusters for each cardiology specialty.

Wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) is a progressive and infiltrative cardiac disorder that may cause fatal consequences if left untreated. The estimated survival time from diagnosis is approximately 3-6 years. Because of the non-specificity of initial symptom manifestation and insufficient awareness among treating physicians, approximately one-third of patients with ATTRwt-CM are initially misdiagnosed with other cardiac diseases. Although heart failure (HF) is the most common initial manifestation of ATTRwt-CM, observed in nearly 70% of affected patients, patients may also present with other cardiologic symptoms, such as atrial fibrillation (AF) and aortic stenosis (AS). This non-specific and diverse nature of the initial ATTRwt-CM presentation indicates that various cardiology subspecialties are involved in patient diagnosis and management. Standard guideline-directed pharmacological treatment for HF is not recommended for patients with ATTRwt-CM because of its limited effectiveness. However, no established algorithms are available regarding HF management in this patient population. This literature review provides an overview of the red flags for ATTRwt-CM and research findings regarding HF management in this patient population. In addition to commonly recognized red flags for ATTRwt-CM (e.g., HF, AF and severe AS), published literature identified potential red flags such as coronary microvascular dysfunction. For HF management in patients with ATTRwt-CM, the use of mineralocorticoid receptor antagonists (MRAs) was reported as a well-tolerated option associated with a low discontinuation rate and reduced mortality. Although there is no concrete evidence for recommendations against sodium-glucose cotransporter 2 inhibitor (SGLT2i) administration, research supporting its use is limited to small-scale studies. Robust evidence is lacking for AF ablation, implantable cardioverter-defibrillators and cardiac resynchronization therapy. Based on the published findings and our clinical experience as Japanese ATTRwt-CM experts, red-flag symptom clusters for each cardiology specialty (HF, arrhythmia and ischaemia/structural heart disease) and a treatment scheme for HF management are presented. As this research area remains at an exploratory stage, our observations would require further discussion among experts worldwide.

Cardiac Amyloidosis: A Comprehensive Review of Pathophysiology, Diagnostic Approach, Applications of Artificial Intelligence, and Management Strategies.

Cardiac amyloidosis (CA) is a serious and often fatal condition caused by the accumulation of amyloid fibrils in the heart, leading to progressive heart failure. It involves the misfolding of normally soluble proteins into insoluble amyloid fibrils, with transthyretin and light-chain amyloidosis being the most common forms affecting the heart. Advances in diagnostics, especially cardiac magnetic resonance imaging and non-invasive techniques, have improved early detection and disease management. Artificial intelligence has emerged as a diagnostic tool for cardiac amyloidosis, improving accuracy and enabling earlier intervention through advanced imaging analysis and pattern recognition. Management strategies include volume control, specific pharmacotherapies like tafamidis, and addressing arrhythmias and advanced heart failure. However, further research is needed for novel therapeutic approaches, the long-term effectiveness of emerging treatments, and the optimization of artificial intelligence applications in clinical practice for better patient outcomes. The article aims to provide an overview of CA, outlining its pathophysiology, diagnostic advancements, the role of artificial intelligence, management strategies, and the need for further research.

Connective tissue amyloidosis in patients referred for orthopedic surgery. CONNECT-AMY study. / Amiloidosis del tejido conectivo en pacientes referidos a cirugía ortopédica. Estudio CONNECT-AMY.

INTRODUCTION AND OBJECTIVE: Clinical manifestations secondary to amyloid deposition in connective tissue may allow early detection of amyloidosis. We sought to identify the prevalence of connective tissue amyloidosis in patients undergoing orthopedic surgery and evaluate for cardiac involvement. MATERIAL AND METHODS: Descriptive cross-sectional study that included patients >50 years referred for orthopedic surgery at our center. A sample of the affected connective tissue was taken during the intervention to evaluate the presence of amyloid material. Those with confirmed amyloidosis were further evaluated with complementary tests for cardiac involvement. RESULTS: Forty-eight patients were included. Mean age was 65.4 years and 41.7% were women. The most frequent surgery was supraspinatus tendon rupture (50%). Transthyretin amyloid deposits were detected in 2 patients (4.2%). The absence of variants in the protein gene established the diagnosis of ATTRwt in both cases. None of them presented cardiac involvement. CONCLUSIONS: In this study, 4.2% of patients referred for orthopedic surgery presented transthyretin amyloidosis in the affected connective tissue.

Recent advances in the diagnostic methods and therapeutic strategies of transthyretin cardiac amyloidosis.

Cardiac amyloidosis is a progressive disease characterized by the buildup of amyloid fibrils in the extracellular space of the heart. It is divided in 2 main types, immunoglobulin light chain amyloidosis and transthyretin amyloidosis (ATTR), and ATTR amyloidosis is further divided in 2 subtypes, non-hereditary wild type ATTR and hereditary mutant variant amyloidosis. Incidence and prevalence of ATTR cardiac amyloidosis is increasing over the last years due to the improvements in diagnostic methods. Survival rates are improving due to the development of novel therapeutic strategies. Tafamidis is the only disease-modifying approved therapy in ATTR amyloidosis so far. However, the most recent advances in medical therapies have added more options with the potential to become part of the therapeutic armamentarium of the disease. Agents including acoramidis, eplontersen, vutrisiran, patisiran and anti-monoclonal antibody NI006 are being investigated on cardiac function in large, multicenter controlled trials which are expected to be completed within the next 2-3 years, providing promising results in patients with ATTR cardiac amyloidosis. However, further and ongoing research is required in order to improve diagnostic methods that could provide an early diagnosis, as well as survival and quality of life of these patients.

Clinical characterization of patients with cardiac amyloidosis in a referral center of Colombia.

Objective: The objective of the study is to describe the characteristics of our first cohort of amyloidosis in a Latin America cardiovascular reference center in Colombia. Methods: This is a historic cohort study and data were taken from the electronic records of the Fundación Cardioinfantil-Instituto de cardiología; adult patients with a diagnosis of cardiac amyloidosis were included and a descriptive analysis was presented. Results: A total of 31 patients with amyloidosis were included. 17 were Transthyretin Amyloidosis (ATTR) subtype and 14 were AL subtype. An overall mortality of 25% was found. The mean age at diagnosis was 74 years, male sex predominant. More frequent comorbidities were hypertension and atrial fibrillation. The most frequent clinical presentation was congestive heart failure (75%), with mildly reduced ejection fraction (41.94%), followed by reduced ejection fraction (32.26%), and preserved ejection fraction (25.81%). In the ATTR subtype, a reduced ejection fraction was found at 41.18% and a mildly reduced ejection fraction at 35.29%. Conclusion: These results provide information on the most frequent type of amyloidosis and the late timing to diagnose in our historic cohort study, we present some of the baseline characteristics and most frequent approaches to diagnose Cardiac Amyloidosis that represents all challenges in clinical practice. Improvements are needed in the diagnosis and early treatment of these patients.

Objetivo: Describir las características de nuestra primera cohorte de amiloidosis en un centro de referencia cardiovascular de Latinoamérica en Colombia. Métodos: Los datos fueron tomados de los registros electrónicos de la Fundación Cardioinfantil- Instituto de cardiología; Se incluyeron pacientes adultos con diagnóstico de amiloidosis cardíaca y se presenta un análisis descriptivo. Resultados: Se incluyeron un total de 31 pacientes con amiloidosis. 17 eran ATTR y 14 eran AL. Se encontró una mortalidad global del 25%. La edad media al diagnóstico fue de 74 años, predominando el sexo masculino. Las comorbilidades más frecuentes fueron Hipertensión y Fibrilación auricular. La presentación clínica más frecuente fue insuficiencia cardíaca congestiva (75%), con fracción de eyección levemente reducida (41.94%), seguida de fracción de eyección reducida (32.26%) y fracción de eyección preservada (25.81%). En el subtipo ATTR, la fracción de eyección reducida se encontró en el 41.18% y la fracción de eyección levemente reducida en el 35.29%. Conclusión: Estos resultados brindan información sobre el tipo de amiloidosis más frecuente y el momento del diagnóstico, el cual fue tardío en nuestra cohorte, su prevalencia en el sexo masculino (61.29%), edad promedio al diagnóstico de 74 años, principal presentación clínica y abordaje más frecuente, mostrando el desafío que representa en la práctica clínica llegar al diagnóstico. Se necesitan mejoras en el diagnóstico y tratamiento precoz de estos pacientes.

Switching from inotersen to eplontersen in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy: analysis from NEURO-TTRansform.

BACKGROUND: The phase 3 NEURO-TTRansform trial showed eplontersen treatment for 65 weeks reduced transthyretin (TTR), halted progression of neuropathy impairment, and improved quality of life (QoL) in adult patients with hereditary TTR-mediated amyloidosis with polyneuropathy (ATTRv-PN), vs. historical placebo. METHODS: NEURO-TTRansform enrolled patients with ATTRv-PN. A subset of patients were randomized to receive subcutaneous inotersen 300 mg weekly (Weeks 1-34) and subsequently switched to subcutaneous eplontersen 45 mg every 4 weeks (Weeks 37-81). Change in serum TTR and treatment-emergent adverse events (TEAEs) were evaluated through Week 85. Effects on neuropathy impairment, QoL, and nutritional status were also evaluated. RESULTS: Of 24 patients randomized to inotersen, 20 (83%) switched to eplontersen at Week 37 and four discontinued due to AEs/investigator decision. Absolute change in serum TTR was greater after switching from inotersen (-74.3%; Week 35) to eplontersen (-80.6%; Week 85). From the end of inotersen treatment, neuropathy impairment and QoL were stable (i.e., did not progress) while on eplontersen, and there was no deterioration in nutritional status. TEAEs were fewer with eplontersen (Weeks 37-85; 19/20 [95%] patients) compared with inotersen (up to Week 35; 24/24 [100%] patients). Mean platelet counts decreased during inotersen treatment (mean nadir reduction ‒40.7%) and returned to baseline during eplontersen treatment (mean nadir reduction, ‒3.2%). CONCLUSIONS: Switching from inotersen to eplontersen further reduced serum TTR, halted disease progression, stabilized QoL, restored platelet count, and improved tolerability, without deterioration in nutritional status. This supports a positive benefit-risk profile for patients with ATTRv-PN who switch from inotersen to eplontersen.