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.

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.

Cardiac amyloidosis (CA) manifests as infiltrative cardiomyopathy with a hypertrophic pattern, usually presenting with heart failure with a preserved ejection fraction. In addition, degenerative valvular heart disease, particularly severe aortic stenosis, is commonly seen in patients with CA. However, amyloid fibril deposition might also infiltrate the conduction system and promote the development of electrical disorders, including ventricular tachyarrhythmias, atrio-ventricular block or acute electromechanical dissociation. These manifestations can increase the risk of sudden cardiac death. This review summarises the pathophysiological mechanisms and risk factors for sudden cardiac death in CA and focuses on the major current concerns regarding medical and device management in this challenging scenario.

Hereditary transthyretin amyloidosis (ATTR) is an autosomal dominant, life-threatening genetic disorder caused by a single-nucleotide variant in the transthyretin gene. This mutation leads to the misfolding and deposition of amyloid in various body organs. Both mutant and wild-type transthyretin contribute to the resulting polyneuropathy and cardiomyopathy, leading to significant sensorimotor disturbances and severe cardiac conditions such as heart failure and arrhythmias, thereby impacting quality of life. Despite several treatments, including orthotopic liver transplantation and transthyretin tetramer stabilizers, their limitations persisted until the introduction of RNA interference (RNAi). RNAi, a means to regulate mRNA stability and translation of targeted genes, has brought about significant changes in treatment strategies for ATTR with the introduction of patisiran in 2018. This study reviews patisiran, vutrisiran, inotersen, and eplontersen, developed for the treatment of ATTR. It provides an overview of the clinical trial outcomes, focusing mainly on quality of life, adverse reactions, and the future of RNAi-based therapies.

BACKGROUND: Transthyretin amyloidosis (ATTR) is a multisystem disease caused by the deposition of fibrillar protein in organs and tissues. ATTR genotypes and phenotypes are highly heterogeneous. We present data on physical signs and symptoms, cardiac and neurological assessments and genetic profile of patients enrolled in the Transthyretin Cardiac Amyloidosis Registry of the State of São Paulo, Brazil.
RESULTS: Six hundred-forty-four patients were enrolled, 505 with the variant form (ATTRv) and 139 with wild-type (ATTRwt). Eleven different mutations were detected, the most common being Val50Met (47.5%) and V142Ile (39.2%). Overall, more than half of the patients presented cardiac involvement, and the difference in this proportion between the ATTRv and ATTRwt groups was significant (43.9 vs. 89.9%; p < 0.001). The prevalence of the neurological phenotype also differed between ATTRv and ATTRwt (56.8 vs. 31.7%; p < 0.001). The mixed phenotype was found in 25.6% of the population, without a significant difference between ATTRv and ATTRwt groups. A group of patients remained asymptomatic (10.4%), with a lower proportion of asymptomatic ATTRwt patients.
CONCLUSIONS: This study details the clinical and genetic spectrum of patients with ATTR in São Paulo, Brazil. This preliminary analysis highlights the considerable phenotypic heterogeneity of neurological and cardiac manifestations in patients with variant and wild-type ATTR.

Amyloidosis is a disease characterized by local and systemic extracellular deposition of amyloid protein fibrils where its excessive accumulation in tissues and resistance to degradation can lead to organ failure. Diagnosis is challenging because of approximately 36 different amyloid protein subtypes. Imaging methods like immunohistochemistry and the use of Congo red staining of amyloid proteins for laser capture microdissection combined with liquid chromatography tandem mass spectrometry (LMD/LC-MS/MS) are two diagnostic methods currently used depending on the expertise of the pathology laboratory. Here, we demonstrate a streamlined in situ amyloid peptide spatial mapping by Matrix Assisted Laser Desorption Ionization-Mass Spectrometry Imaging (MALDI-MSI) combined with Trapped Ion Mobility Spectrometry for potential transthyretin (ATTR) amyloidosis subtyping. While we utilized the standard LMD/LC-MS/MS workflow for amyloid subtyping of 31 specimens from different organs, we also evaluated the potential introduction in the MS workflow variations in data acquisition parameters like dynamic exclusion, or testing Data Dependent Acquisition combined with High-Field Asymmetric Waveform Ion Mobility Spectrometry (DDA FAIMS) versus Data Independent Acquisition (DIA) for enhanced amyloid protein identification at shorter acquisition times. We also demonstrate the use of Mascot\'s Error Tolerant Search and PEAKS de novo sequencing for the sequence variant analysis of amyloidosis specimens.

BACKGROUND: Results from ATTR-ACT (Safety and Efficacy of Tafamidis in Patients With Transthyretin Cardiomyopathy) indicate that tafamidis prolongs survival and reduces cardiovascular hospitalizations in cardiac transthyretin amyloidosis (ATTR-CA). However, real-world data supporting these findings are scarce. Thus, we sought to characterize the clinical outcome of patients with ATTR-CA treated with tafamidis in a real-world setting and assess the prognostic role of the New York Heart Association (NYHA) classification.
RESULTS: We conducted a retrospective observational study, enrolling a consecutive sample of patients with ATTR-CA (wild-type or variant) treated with tafamidis. Clinical outcome was tracked through follow-up visits or phone calls. Primary outcomes were death and major adverse cardiac events (MACE), a composite end point of death and hospitalizations for acute cardiac decompensation, myocardial infarction, severe arrythmias, or stroke. Kaplan-Meier analysis estimated overall and MACE-free survival including NYHA subgroups (NYHA I/II versus NYHA III). One hundred sixty-seven patients with ATTR-CA (94.6% wild-type) were enrolled and followed for a median of 539 [323-869] days. Median overall survival was not reached. Estimated 1-year, 2-year, and 5-year overall survival among the whole cohort was 93.5%, 85.9%, and 70.2%, respectively. Overall survival was higher in the NYHA I/II subgroup (P=0.002). Median MACE-free survival time was 1082 (95% CI, 962-1202) days. MACE-free survival was higher in the NYHA I/II subgroup (P<0.001). With respective hazard ratios of 5.85 (95% CI, 1.48-23.18; P=0.012) and 3.95 (95% CI, 1.99-7.84; P<0.001), NYHA III was an independent predictor of death and MACE.
CONCLUSIONS: Treatment of ATTR-CA with tafamidis led to substantial improvements of clinical outcome. NYHA classification at treatment initiation is a reliable tool to provide patients with individualized prognostic information.

UNASSIGNED: Previous literature suggests that patients with transthyretin amyloidosis (ATTR) experience a high burden of ventricular arrhythmias. Despite this evidence, optimal strategies for arrhythmia prevention and treatment remain subject to debate.
UNASSIGNED: We report the case of a patient with hereditary ATTR cardiomyopathy who developed recurrent ventricular tachycardia prior to a decline in his left ventricular ejection fraction (LVEF). Although he ultimately received an intracardiac device (ICD) for secondary prevention of ventricular tachycardia, his clinical course begets the question of whether more aggressive arrhythmia prevention upfront could have prevented his global functional decline.
UNASSIGNED: Given the advent of new disease-modifying therapies for ATTR, it is imperative to reconsider antiarrhythmic strategies in these patients. New decision tools are needed to decide what additional parameters (beyond LVEF ≤ 35%) may warrant ICD placement for primary prevention of ventricular arrhythmias in these patients.

BACKGROUND: Hereditary transthyretin amyloidosis (ATTRv, also referred to as hATTR; ORPHA 271861) and wild-type ATTR amyloidosis (ATTRwt; ORPHA 330001) are rare, progressive, systemic protein misfolding disorders with heterogeneous clinical presentations. ATTRv and ATTRwt amyloidosis are characterized by the deposition of amyloid fibrils in multiple organs including the heart, nerves, eyes, and soft tissues. The management of ATTR amyloidosis is complex because of its multisystemic nature and progression despite available treatment options. Morbidity is high and there are many unmet medical needs for patients. While contemporary ATTR amyloidosis cohorts are diagnosed earlier, have lower risk disease and lower mortality compared with the previous era, these advances coupled with the emergence of effective disease-modifying therapies have confounded the design of future prospective clinical trials and interpretation of historical control data.
METHODS: The Amyloidosis Forum is a public-private partnership between the US Food and Drug Administration Center for Drug Evaluation and Research and the nonprofit Amyloidosis Research Consortium ( www.arci.org ). This article summarizes proceedings from the 21 June 2023 Amyloidosis Forum on advancing drug development in ATTR amyloidosis in an evolving treatment landscape. The Forum focused on elements of clinical trial design to address these challenges and discussed their strengths and weaknesses from multiple stakeholder perspectives (i.e., patient, sponsor, statistician, clinician, and regulatory authorities).
CONCLUSIONS: Given rapid evolution of natural history in ATTR amyloidosis, the utility of historical control data is limited. Leveraging contemporary real-world data is essential for clinical trial design. Evidence generation from clinical trials should address clinically relevant questions. Key factors in successful trial design must be informed by up-to-date data on natural history, prognostic factors, clinically meaningful thresholds, and sharing available clinical trial data. The Amyloidosis Forum includes the community of patients with ATTR amyloidosis, the physicians who treat them, and the sponsors and regulators who collectively stand ready to support further studies in order to develop novel effective therapies.

Transthyretin cardiac amyloidosis (ATTR-CA) is a condition characterized by extracellular deposition of misfolded transthyretin proteins in the myocardium and has been historically difficult to diagnose due to diverse clinical manifestations and nonspecific, variable electrocardiogram (ECG) and echocardiogram findings. Advancements in noninvasive cardiac imaging have led to significant increases in diagnoses of ATTR-CA. Once thought to be a rare condition, there is growing evidence to suggest that ATTR-CA is more prevalent than previously understood, prompting the need for early diagnosis and intervention. We outline the case of a 78-year-old male who presented to the emergency department with chest discomfort, shortness of breath, dizziness, and diaphoresis. He was found to have severe coronary artery disease (CAD) and intermittent complete heart block. Cardiac dysfunction was unable to be resolved by percutaneous coronary intervention (PCI) and thus the patient was referred for coronary artery bypass grafting (CABG). Intraoperatively, the patient\'s heart was found to be abnormally thickened and fibrosed. Biopsy of the cardiac tissue and evaluation using technetium-99m pyrophosphate scintigraphy, single-photon emission computed tomography, and liquid chromatography-tandem mass spectrometry revealed ATTR-CA. There is a need for fast and low-cost screening tools to allow for early identification of the disease. Diagnostic clues for cardiac amyloidosis include the presence of carpal tunnel syndrome, lumbar spinal stenosis, atrial fibrillation, treatment-resistant heart failure with preserved ejection fraction, and a thickened left ventricular wall. Given the presence of these red flag symptoms, clinicians should have a heightened index of suspicion for ATTR cardiac amyloidosis in elderly patients even when presenting in acute settings.