or transthyretin (ATTR) 2-4 types in the vast majority of cases. ATTR amyloidosis may be acquired, associated with wild-type Background-Cardiac transthyretin (ATTR) amyloidosis is a progressive and fatal cardiomyopathy for which several promising therapies are in development. The diagnosis is frequently delayed or missed because of the limited specificity of echocardiography and the traditional requirement for histological confirmation. It has long been recognized that technetium-labeled bone scintigraphy tracers can localize to myocardial amyloid deposits, and use of this imaging modality for the diagnosis of cardiac ATTR amyloidosis has lately been revisited. We conducted a multicenter study to ascertain the diagnostic value of bone scintigraphy in this disease. Methods and Results-Results of bone scintigraphy and biochemical investigations were analyzed from 1217 patients with suspected cardiac amyloidosis referred for evaluation in specialist centers. Of 857 patients with histologically proven amyloid (374 with endomyocardial biopsies) and 360 patients subsequently confirmed to have nonamyloid cardiomyopathies, myocardial radiotracer uptake on bone scintigraphy was >99% sensitive and 86% specific for cardiac ATTR amyloid, with false positives almost exclusively from uptake in patients with cardiac AL amyloidosis. Importantly, the combined findings of grade 2 or 3 myocardial radiotracer uptake on bone scintigraphy and the absence of a monoclonal protein in serum or urine had a specificity and positive predictive value for cardiac ATTR amyloidosis of 100% (positive predictive value confidence interval, 98.0-100). Conclusions-Bone scintigraphy enables the diagnosis of cardiac ATTR amyloidosis to be made reliably without the need for histology in patients who do not have a monoclonal gammopathy. We propose noninvasive diagnostic criteria for cardiac ATTR amyloidosis that are applicable to the majority of patients with this disease. Clinical Perspective on p 2412Autopsy studies have shown the presence of cardiac ATTR amyloid deposits in up to 25% of individuals >80 years of age, although in many of these hearts the amount of amyloid was small.8 Nevertheless, among patients with heart failure and preserved ejection fraction, postmortem examination indicates that cardiac amyloid deposition is commoner than in an age-matched autopsy group without heart failure. The majority of patients with cardiac amyloid on postmortem in these studies had not had amyloidosis diagnosed during their lifetime.9 Echocardiography, although a valuable and widely accessible tool for investigating heart failure, is neither sensitive nor specific for cardiac amyloidosis.10 Typical findings on echocardiography include thickening of ventricular walls, restrictive filling, abnormal left and right ventricular longitudinal strain, and atrial septal thickening.11 Cardiac magnetic resonance imaging (CMR) has much greater diagnostic value in cardiac amyloidosis, but false-positive and false-negative CMRs are not infrequent.12 Typical findings ...

This study identifies and validates new criteria for response to first-line treatment in AL amyloidosis, based on their association with survival in large patient populations, and offers surrogate end points for clinical trials.

Systemic immunoglobulin light chain (AL) amyloidosis is a protein misfolding disease that is caused by the conversion of immunoglobulin light chains from their soluble functional states into highly organized amyloid fibrillar aggregates that lead to organ dysfunction. The disease is progressive and, accordingly, early diagnosis is vital to prevent irreversible organ damage, of which cardiac and renal damage predominate. The development of novel sensitive biomarkers and imaging technologies for the detection and quantification of organ involvement and damage are facilitating earlier diagnosis and enhanced evaluation of the efficacy of new and existing therapies. Treatment is guided by risk assessment which is based on levels of cardiac biomarkers; close monitoring of clonal and organ response guides duration of therapy and changes in regimen. Several new classes of drugs, such as proteasome inhibitors and immunomodulatory drugs, along with high-dose chemotherapy and autologous haematopoietic stem cell transplantation, have led to rapid and deep suppression of the amyloid light chain production in the majority of patients. However, effective therapies for patients with advanced cardiac involvement are an unmet need. Passive immunotherapies targeting clonal plasma cells and directly accelerating removal of amyloid deposits promise to further improve the overall outlook of this increasingly treatable disease.

Key Points• A staging system based on proteinuria and glomerular filtration rate discriminates patients at different risk of progression to dialysis.• Changes in proteinuria and glomerular filtration rate allow early assessment of renal response to therapy.The kidney is involved in 70% of patients with immunoglobulin light-chain (AL) amyloidosis, but little is known on progression or reversibility of renal involvement, and criteria for renal response have never been validated. Newly diagnosed patients from the Pavia (n 5 461, testing cohort) and Heidelberg (n 5 271, validation cohort) centers were included. Proteinuria >5 g/24 h and estimated glomerular filtration rate (eGFR) <50 mL/min predicted progression to dialysis best. Proteinuria below and eGFR above the thresholds indicated low risk (0 and 4% at 3 years in the testing and validation cohorts, respectively). High proteinuria and low eGFR indicated high risk (60% and 85% at 3 years). At 6 months, a ‡25% eGFR decrease predicted poor renal survival in both cohorts and was adopted as criterion for renal progression. A decrease in proteinuria by ‡30% or below 0.5 g/24 h without renal progression was the criterion for renal response, being associated with longer renal survival in the testing and validation populations. Hematologic very good partial or complete remission at 6 months improved renal outcome in both populations. We identified and validated a staging system for renal involvement and criteria for early assessment of renal response and progression in AL amyloidosis that should be used in clinical practice and trial design. (Blood. 2014;124(15):2325-2332