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Transthyretin amyloidosis, also called ATTR amyloidosis, is associated with accumulation of ATTR amyloid deposits in the heart and commonly manifests as progressive cardiomyopathy. Patisiran, an RNA interference therapeutic agent, inhibits the production of hepatic transthyretin. In this phase 3, double-blind, randomized trial, we assigned patients with hereditary, also known as variant, or wild-type ATTR cardiac amyloidosis, in a 1:1 ratio, to receive patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks for 12 months. A hierarchical procedure was used to test the primary and three secondary end points. The primary end point was the change from baseline in the distance covered on the 6-minute walk test at 12 months. The first secondary end point was the change from baseline to month 12 in the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score (with higher scores indicating better health status). The second secondary end point was a composite of death from any cause, cardiovascular events, and change from baseline in the 6-minute walk test distance over 12 months. The third secondary end point was a composite of death from any cause, hospitalizations for any cause, and urgent heart failure visits over 12 months. A total of 360 patients were randomly assigned to receive patisiran (181 patients) or placebo (179 patients). At month 12, the decline in the 6-minute walk distance was lower in the patisiran group than in the placebo group (Hodges-Lehmann estimate of median difference, 14.69 m; 95% confidence interval [CI], 0.69 to 28.69; P = 0.02); the KCCQ-OS score increased in the patisiran group and declined in the placebo group (least-squares mean difference, 3.7 points; 95% CI, 0.2 to 7.2; P = 0.04). Significant benefits were not observed for the second secondary end point. Infusion-related reactions, arthralgia, and muscle spasms occurred more often among patients in the patisiran group than among those in the placebo group. In this trial, administration of patisiran over a period of 12 months resulted in preserved functional capacity in patients with ATTR cardiac amyloidosis. (Funded by Alnylam Pharmaceuticals; APOLLO-B ClinicalTrials.gov number, NCT03997383.).

In a randomized trial of bortezomib, cyclophosphamide, and dexamethasone as compared with the same therapy plus daratumumab, patients with light-chain amyloidosis who received daratumumab had a higher frequency of hematologic complete response than those who did not (53.3% vs. 18.1%). Deaths were most commonly due to cardiac failure.

Cardiac amyloidosis is an infiltrative cardiomyopathy characterized by the abnormal accumulation of amyloid proteins within the heart muscle. It is recognized as a rare yet significant cardiac disease that is often overlooked as a potential cause of heart failure and cardiac arrhythmias, particularly in older individuals with rates escalating from 8 to 17 cases per 100,000 individuals. Cardiac amyloidosis primarily manifests as two predominant subtypes: light-chain and transthyretin amyloidosis, collectively accounting for over 95% of clinical cases. Early diagnosis of these conditions is often hindered by overlapping symptoms with other cardiac pathologies, resulting in diagnostic delays and suboptimal patient outcomes. Echocardiography, a non-invasive imaging technique, has become indispensable for diagnosing cardiac amyloidosis, uncovering crucial echocardiographic signs such as thickening of the left ventricular wall, diastolic dysfunction, and a granular appearance of the myocardium. Recent advancements in echocardiography have significantly enhanced the diagnostic accuracy of cardiac amyloidosis and improved patient management. Advanced echocardiographic techniques, including strain imaging, 3D echocardiography, and contrast echocardiography, have significantly enhanced diagnostic accuracy and prognostication. Future directions in echocardiography encompass the integration of artificial intelligence, the development of novel contrast agents, and the refinement of 4D echocardiography to further optimize patient care. This study explores the pivotal role of echocardiography in both diagnosing and managing cardiac amyloidosis, delving into the disease’s underlying mechanisms, distinctive imaging characteristics, the significance of regular echocardiographic assessments, and discusses the challenges associated with differentiating between various types of amyloidosis without supplemental imaging or biopsy methods. Graphical abstract

Transthyretin amyloid cardiomyopathy is characterized by the deposition of misfolded monomeric transthyretin (TTR) in the heart. Acoramidis is a high-affinity TTR stabilizer that acts to inhibit dissociation of tetrameric TTR and leads to more than 90% stabilization across the dosing interval as measured ex vivo. In this phase 3, double-blind trial, we randomly assigned patients with transthyretin amyloid cardiomyopathy in a 2:1 ratio to receive acoramidis hydrochloride at a dose of 800 mg twice daily or matching placebo for 30 months. Efficacy was assessed in the patients who had an estimated glomerular filtration rate of at least 30 ml per minute per 1.73 m of body-surface area. The four-step primary hierarchical analysis included death from any cause, cardiovascular-related hospitalization, the change from baseline in the N-terminal pro-B-type natriuretic peptide (NT-proBNP) level, and the change from baseline in the 6-minute walk distance. We used the Finkelstein-Schoenfeld method to compare all potential pairs of patients within strata to generate a P value. Key secondary outcomes were death from any cause, the 6-minute walk distance, the score on the Kansas City Cardiomyopathy Questionnaire-Overall Summary, and the serum TTR level. A total of 632 patients underwent randomization. The primary analysis favored acoramidis over placebo (P<0.001); the corresponding win ratio was 1.8 (95% confidence interval [CI], 1.4 to 2.2), with 63.7% of pairwise comparisons favoring acoramidis and 35.9% favoring placebo. Together, death from any cause and cardiovascular-related hospitalization contributed more than half the wins and losses to the win ratio (58% of all pairwise comparisons); NT-proBNP pairwise comparisons yielded the highest ratio of wins to losses (23.3% vs. 7.0%). The overall incidence of adverse events was similar in the acoramidis group and the placebo group (98.1% and 97.6%, respectively); serious adverse events were reported in 54.6% and 64.9% of the patients. In patients with transthyretin amyloid cardiomyopathy, the receipt of acoramidis resulted in a significantly better four-step primary hierarchical outcome containing components of mortality, morbidity, and function than placebo. Adverse events were similar in the two groups. (Funded by BridgeBio Pharma; ATTRibute-CM ClinicalTrials.gov number, NCT03860935.).

Background Characteristics of AL amyloidosis across Asia are not well-described in the literature. Thus, we overviewed the incidence and disease characteristics of AL amyloidosis in Korea. Methods We collected medical records of 302 AL amyloidosis patients and compared survival outcomes by predominant treatment strategy and at four time points: 1995–2003, 2004–2008, 2009–2013, and 2014–2018. Results The median age was 62 years (36–83). One hundred forty-one patients were classified as stage III (26.3%) or IV (47.9%). The patients diagnosed between 2014 and 2018 survived longer than those diagnosed at other time points due to the introduction of bortezomib ( p  < 0.01). In addition, patients who received upfront ASCT survived longer than those who received salvage ASCT or chemotherapy alone ( p  < 0.01). However, most of the 85 patients who experienced early death within 6 months were older than 75 years, had BMI less than 20, and had a high disease burden. Conclusions The incidence of AL amyloid has increased and survival outcomes have improved gradually, most likely due to introduction of novel agents and upfront ASCT. However, not all patients are suitable for these potent treatment modalities, and avoiding early death within 6 months remains a challenge.

The perspective on cardiac amyloidosis has deeply changed over the last 10 years following major advances in diagnosis and treatment options. This heterogeneous disease requires the interaction among experts of different specialties and subspecialties. Suspicion of disease, timely recognition and confirmation of final diagnosis, prognostic stratification, overall management and therapeutic strategies represent ongoing challenges in the clinical setting. Missing or delayed diagnosis may have significant impact on patient outcome, especially in light-chain amyloidosis. The present inter-society consensus document aims to provide a standardized approach to the diagnosis of cardiac amyloidosis in Italy, and to discuss the challenging clinical scenarios encountered in routine activity for cardiologists and physicians of different specialties dealing with patients with suspected or established cardiac amyloidosis. This document may be adapted to the setting of each specific region.

Light chain (AL) amyloidosis is a rare systemic disease caused by monoclonal immunoglobulin light chains with abnormal folding that aggregate into fibrils, which deposit in extracellular tissues. This process leads to cytotoxicity and organ dysfunction. Cardiac involvement is the main prognostic determinant and requires a multidisciplinary management approach. In recent years, the treatment of AL amyloidosis has significantly evolved with the introduction of innovative agents such as proteasome inhibitors, immunomodulators, and monoclonal antibodies like daratumumab, which has shown a favorable impact on hematological outcomes and organ function. The daratumumab-CyBorD regimen is currently the standard first-line therapeutic option. The therapy is tailored based on the stage of cardiac and renal damage, aiming for a complete hematological and organ response. The management of cardiac involvement, including aortic stenosis, atrial fibrillation, thromboembolic risk, conduction disorders, arrhythmias, and heart failure, plays a crucial role in prognosis. An integrated multidisciplinary approach in specialized centers experienced in the disease is essential to optimize clinical outcomes.

Malnutrition is associated with mortality and impaired quality of life (QoL) in systemic immunoglobulin light-chain (AL) amyloidosis. The aim of this study was to determine whether nutritional counseling is beneficial to patients with AL. In this intervention study (ClinicalTrials.gov Identifier: NCT02055534), 144 treatment-naïve outpatients with AL were randomized to usual care (UC; n = 72) and nutritional counseling (NC; n = 72). In the randomized population, although patients in the NC group maintained a stable body weight (weight loss [WL] = 0.6 kg; 95% confidence interval [CI], −1.0 to 2.1; P = 0.214), those in the UC group demonstrated a significant decrease (WL = 2.1 kg; 95% CI, 0.2–4.1; P = 0.003). However, the difference in weight between groups was not significant (mean WL difference = 1.6 kg; 95% CI, −0.7 to 3.9; P = 0.179). Patients in the NC group demonstrated more satisfactory energy intake (≥75% of estimated requirements, odds ratio, 2.18; 95% CI, 1.04–4.57; P = 0.048) and a significant increase in the mental component summary of QoL (Short form-36) at 12 mo (mean difference, 8.1; 95% CI, 2.3–13.9; P = 0.007), which was restored to a mean score of 53 (95% CI, 50–53), over the healthy population norms. NC was also associated with better survival (crude hazard ratio, 0.57; 95% CI, 0.35–0.94; P = 0.028). In outpatients with AL, NC was helpful in preserving body weight, effective in improving mental QoL, and associated with better survival. •We investigated whether nutritional counseling is beneficial to patients with systemic immunoglobulin light-chain amyloidosis.•Nutritional counseling was helpful in preserving body weight in these patients.•Nutritional counseling was effective in improving the mental quality of life of these patients.•Nutritional counseling was associated with better survival in patients with systemic immunoglobulin light-chain amyloidosis.

Diagnosis of hereditary transthyretin-related amyloidosis (ATTR) is challenging owing to its extremely heterogeneous phenotype. The existence of predominantly cardiac presentations should prompt cardiologists to consider ATTR in patients with otherwise unexplained left ventricular wall thickening. Orthotopic liver transplantation (or combined heart–liver transplantation) can potentially provide surgical 'gene therapy' in patients with ATTR, provided that diagnosis is timely. A nonhereditary form of systemic amyloidosis associated with wild-type transthyretin causes heart involvement predominantly in elderly men (systemic senile amyloidosis, or SSA). However, hereditary transthyretin-related amyloidosis (ATTR) is the most frequent form of familial systemic amyloidosis, a group of severe diseases with variable neurological and organ involvement. ATTR remains a challenging and widely underdiagnosed condition, owing to its extreme phenotypic variability: the clinical spectrum of the disease ranges from an almost exclusive neurologic involvement to a strictly cardiac presentation. Such heterogeneity principally results from differential effects of the various reported transthyretin mutations, the geographic region the patient is from and, in the case of the most common mutation, Val30Met, whether or not large foci of cases occur (endemic versus nonendemic aggregation). Genetic or environmental factors (such as age, sex, and amyloid fibril composition) also contribute to the heterogeneity of ATTR, albeit to a lesser extent. The existence of exclusively or predominantly cardiac phenotypes should lead clinicians to consider the possibility of ATTR in all patients who present with an unexplained increase in left ventricular wall thickness at echocardiography. Assessment of such patients should include an active search for possible red flags that can point to the correct final diagnosis. Key Points Amyloidotic cardiomyopathy is a challenging condition that can mimic many other diseases, such as hypertrophic cardiomyopathy or coronary artery disease Hereditary transthyretin-related amyloidosis (ATTR) is the most frequent form of familial systemic amyloidosis The clinical spectrum of ATTR ranges from almost exclusive neurologic involvement within a clearly familial context, to apparently sporadic cases with a strictly cardiac presentation Phenotypic heterogeneity is linked to at least three different factors: the type of transthyretin mutation, geographic region, and the type of Val30Met aggregation (endemic or nonendemic) Diagnosis of ATTR-related amyloidotic cardiomyopathy generally involves electrocardiography and echocardiography; the specific clinical signs can be very mild and may be missed by the patient Orthotopic liver transplantation or combined heart–liver transplantation can provide surgical 'gene therapy' for amyloidotic cardiomyopathy; the combined procedure can be offered to patients with severe heart failure

Cardiac amyloidosis (CA) is a condition caused by extracellular deposition of amyloid fibrils in the heart. It is an underdiagnosed disease entity which can present with a variety of cardiac and non-cardiac manifestations. Diagnosis usually follows an initial suspicion based on clinical evaluation or imaging findings before confirmation with subsequent imaging (echocardiography, cardiac magnetic resonance imaging, 3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy) in combination with biochemical screening for monoclonal dyscrasia (serum free light chains and serum and urine electrophoresis) and/or histology (bone marrow trephine, fat or endomyocardial biopsy). More than 95% of CA can be classified as either amyloid light-chain (AL) CA or amyloid transthyretin (ATTR) CA; these two conditions have very different management strategies. AL-CA, which may be associated with multiple myeloma, can be managed with chemotherapy agents, autologous stem cell transplantation, cardiac transplant and supportive therapies. For ATTR-CA, there is increasing importance in making an early diagnosis because of novel treatments in development, which have transformed this once incurable disease to a potentially treatable disease. Timely diagnosis is crucial as there may only be a small window of opportunity where patients can benefit from treatment beyond which therapies may be less effective. Reviewing the existing patient pathway provides a basis to better understand the complexities of real-world activities which may be important to help reduce missed opportunities related to diagnosis and treatment for patients with CA. With healthcare provider interest in improving the care of patients with CA, the development of an optimal care pathway for the condition may help reduce delays in diagnosis and treatment and thus enhance patient outcomes.