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Diagnosis and treatment of cardiac amyloidosis have rapidly evolved over the past decade by harnessing mechanisms of disease pathogenesis. Cardiac amyloidosis is caused by myocardial deposition of fibrils formed by misfolded proteins, namely transthyretin (ATTR) and immunoglobulin light chains (AL). Advances in noninvasive imaging have revolutionized diagnosis of ATTR cardiomyopathy (CM). Novel treatments for ATTR-CM utilize a range of therapeutic techniques, including protein stabilizers, interfering RNA, gene editing, and monoclonal antibodies. AL-CM, primarily driven by plasma cell dyscrasias, requires treatment with chemotherapy and consideration for autologous stem cell transplant. These incredible advances aim to improve patient outcomes in cardiac amyloidosis., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Cardiac amyloidosis (CA) is related to the aggregation of insoluble fibrous deposits of misfolded proteins within the myocardium. Transthyretin amyloidosis (ATTR) and immunoglobulin light-chain amyloidosis are the main forms of CA. Atrial fibrillation (AF) is a common arrhythmia in CA patients, especially in those with ATTR amyloidosis. Increased atrial preload and afterload, atrial enlargement, enhanced atrial wall stress, and autonomic dysfunction are the main mechanisms of AF in CA patients. CA is associated with the formation of endocardial thrombi and systemic embolism. The promoters of thrombogenesis include endomyocardial damage, blood stasis, and hypercoagulability. The prevalence of thrombi in patients with AF remains elevated despite long-term anticoagulation. Consequently, transesophageal ultrasound examinations before cardioversion should be performed to exclude endocardiac thrombi despite anticoagulation. Furthermore, the CHA 2 DS 2 -VASc score should not be used to assess the thromboembolic risk in CA patients with AF. Rate control is challenging in patients with CA, while rhythm control is the preferred treatment option, especially in the early stages of the disease process. Although catheter ablation is an effective treatment option, more data are needed to explore the role of the procedure in CA patients., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Amyloidosis is a disease caused by misfolded proteins that deposit in the extracellular matrix as fibrils, resulting in the dysfunction of the involved organ. The lung is a common target of Amyloidosis, but pulmonary amyloidosis is uncommonly diagnosed since it is rarely symptomatic. Diagnosis of pulmonary amyloidosis is usually made in the setting of systemic amyloidosis, however in cases of localized pulmonary disease, surgical or transbronchial tissue biopsy might be indicated. Pulmonary amyloidosis can be present in a variety of discrete entities. Diffuse Alveolar septal amyloidosis is the most common type and is usually associated with systemic AL amyloidosis. Depending on the degree of the interstitial involvement, it may affect alveolar gas exchange and cause respiratory symptoms. Localized pulmonary Amyloidosis can present as Nodular, Cystic or Tracheobronchial Amyloidosis which may cause symptoms of airway obstruction and large airway stenosis. Pleural effusions, mediastinal lymphadenopathy and pulmonary hypertension has also been reported. Treatment of all types of pulmonary amyloidosis depends on the type of precursor protein, organ involvement and distribution of the disease. Most of the cases are asymptomatic and require only close monitoring. Diffuse alveolar septal amyloidosis treatment follows the treatment of underlying systemic amyloidosis. Tracheobronchial amyloidosis is usually treated with bronchoscopic interventions including debulking and stenting or with external beam radiation. Long-term prognosis of pulmonary amyloidosis usually depends on the type of lung involvement and other organ function., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Cardiac amyloidosis (CA) is an underdiagnosed disease that is caused by deposition of misfolded transthyretin (ATTR) or immunoglobulin light chain (AL) fibrils in the myocardium. Bradyarrhythmias are commonly seen in CA, due to disruption of conducting system by amyloid fibrils. Atrioventricular conduction defect is more common than sinus node dysfunction. Bradyarrhythmias are most prevalent in wtATTR, followed by hATTR and AL. Pacemaker implantation, when indicated, can help provide symptomatic relief but does not confer mortality benefit. Progression of conduction system disease is common and often leads to increased right ventricular pacing burden with time. Therefore, cardiac resynchronizing therapy (biventricular therapy) is often considered as a better and safer option in these patients. Finally, the role of prophylactic pacemaker implantation is controversial, and current guidelines do not recommend prophylactic pacemaker insertion in CA patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Cardiac amyloidosis is an underdiagnosed disease that is caused by myocardial deposition of misfolded light chain (AL) or transthyretin (ATTR) amyloid fibrils, leading to restrictive cardiomyopathy and eventually death if untreated. Ventricular arrhythmias are common in cardiac amyloidosis, and the prevalence is higher in AL than ATTR. There are multiple suspected pathogenic mechanisms for ventricular arrhythmia including activation of inflammatory cascade from direct amyloid deposition, and electro-mechanical as well as autonomic dysfunction due to systemic amyloid deposition. Cardiac amyloidosis is associated with an increased risk of sudden cardiac death, and the risk is higher in AL than ATTR. Finally, the role of implantable cardioverter-defibrillators in cardiac amyloidosis is controversial, and while successful termination of life-threatening ventricular arrhythmias has been reported in few studies, there has been no evidence of improvement in outcomes when used for primary prevention in patients with cardiac amyloidosis., Competing Interests: Declaration of competing interest The authors have no disclosures., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

AA amyloidosis is secondary to the deposit of excess insoluble Serum Amyloid A (SAA) protein fibrils. AA amyloidosis complicates chronic inflammatory diseases, especially chronic inflammatory rheumatisms such as rheumatoid arthritis and spondyloarthritis; chronic infections such as tuberculosis, bronchectasia, chronic inflammatory bowel diseases such as Crohn's disease; and auto-inflammatory diseases including familial Mediterranean fever. This work consists of the French guidelines for the diagnosis workup and treatment of AA amyloidosis. We estimate in France between 500 and 700 cases in the whole French population, affecting both men and women. The most frequent organ impaired is kidney which usually manifests by oedemas of the lower extremities, proteinuria, and/or renal failure. Patients are usually tired and can display digestive features anf thyroid goiter. The diagnosis of AA amyloidosis is based on detection of amyloid deposits on a biopsy using Congo Red staining with a characteristic green birefringence in polarized light. Immunohistochemical analysis with an antibody directed against Serum Amyloid A protein is essential to confirm the diagnosis of AA amyloidosis. Peripheral inflammatory biomarkers can be measured such as C Reactive protein and SAA. We propose an algorithm to guide the etiological diagnosis of AA amyloidosis. The treatement relies on the etiologic treatment of the undelying chronic inflammatory disease to decrease and/or normalize Serum Amyloid A protein concentration in order to stabilize amyloidosis. In case of renal failure, dialysis or even a kidney transplant can be porposed. Nowadays, there is currently no specific treatment for AA amyloidosis deposits which constitutes a therapeutic challenge for the future., (Copyright © 2022 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Amyloidosis is a group of disorders that can affect almost any organ due to the misfolding of proteins with their subsequent deposition in various tissues, leading to various disease manifestations based on the location. When the heart is involved, amyloidosis can manifest with a multitude of presentations such as heart failure, arrhythmias, orthostatic hypotension, syncope, and pre-syncope. Diagnosis of cardiac amyloidosis can be difficult due to the non-specific nature of symptoms and the relative rarity of the disease. Amyloidosis can remain undiagnosed for years, leading to its high morbidity and mortality due to this delay in diagnosis. Newer imaging modalities, such as cardiac magnetic resonance imaging, advanced echocardiography, and biomarkers, make a timely cardiac amyloidosis diagnosis more feasible. Many treatment options are available, which have provided new hope for this patient population. This manuscript will review the pathology, diagnosis, and treatment options available for cardiac amyloidosis and provide a comprehensive overview of this complicated disease process., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome, and cardiac amyloidosis (CA) is one of the causes of HFpEF, that has established and emerging treatment options. However, it remains an underdiagnosed and often overlooked cause of HFpEF. The importance of early diagnosis cannot be emphasized enough, as emerging therapies are more effective early in the course of the disease. Further, because of the unique physiologic and hemodynamic features of CA, patients poorly tolerate traditional heart failure medications and experience worse outcomes compared with other causes of HFpEF. With the aging of the population, transthyretin (ATTR) CA, once thought to be a rare disease, will become the most common type of systemic amyloidosis. ATTR-CA is increasingly recognized due to enhanced clinical awareness; advances in diagnostic imaging that have led to a diagnostic approach that does not require a biopsy, as well as the recent introduction of novel disease-modifying treatments. ATTR-CA causes restrictive and infiltrative cardiomyopathy that results in heart failure, atrial and ventricular arrhythmias, and conduction disease, and is associated with significant morbidity and mortality. Our goal in this review is to provide an overview of the historical, epidemiologic, diagnostic, and therapeutic evolution of ATTR-CA, and to emphasize the importance of early suspicion and detection of HFpEF., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Mitral regurgitation (MR) and cardiac amyloidosis (CA) both primarily affect older patients. Data on coexistence and prognostic implications of MR and CA are currently lacking., Objectives: This study sought to identify the prevalence, clinical characteristics, and outcomes of MR CA compared with lone MR., Methods: Consecutive patients undergoing transcatheter edge-to-edge repair (TEER) for MR at 2 sites were screened for concomitant CA using a multiparametric approach including core laboratory 99m Tc-3,3-diphosphono-1,2-propanodicarboxylic acid bone scintigraphy and echocardiography and immunoglobulin light chain assessment. Transthyretin CA (ATTR) was diagnosed by 99m Tc-3,3-diphosphono-1,2-propanodicarboxylic acid (Perugini grade 1: early infiltration; grades 2/3: clinical CA) and the absence of monoclonal protein, and light chain (AL) CA via tissue biopsy. All-cause mortality and hospitalization for heart failure (HHF) served as the endpoints., Results: A total of 120 patients (age 76.9 ± 8.1 years, 55.8% male) were recruited. Clinical CA was diagnosed in 14 patients (11.7%; 12 ATTR, 1 AL, and 1 combined ATTR/AL) and early amyloid infiltration in 9 patients (7.5%). Independent predictors of MR CA were increased posterior wall thickness and the presence of a left anterior fascicular block on electrocardiography. Procedural success and periprocedural complications of TEER were similar in MR CA and lone MR (P for all = NS). After a median of 1.7 years, 25.8% had experienced death and/or HHF. MR CA had worse outcomes compared with lone MR (HR: 2.2; 95% CI: 1.0-4.7; P = 0.034), driven by a 2.5-fold higher risk for HHF (HR: 2.5; 95% CI: 1.1-5.9), but comparable mortality (HR: 1.6; 95% CI: 0.4-6.1)., Conclusions: Dual pathology of MR CA is common in elderly patients with MR undergoing TEER and has worse postinterventional outcomes compared with lone MR., Competing Interests: Funding Support and Author Disclosures This study received financial support from Pfizer. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The treatment of patients with systemic light chain (AL) amyloidosis is a challenge to hematologists. Despite its generally small size, the underlying clone causes a rapidly progressing, often devastating multiorgan dysfunction through the toxic light chains that form amyloid deposits. Clinical manifestations are deceitful and too often recognized at an irreversible stage. However, hematologists are in the unique position to diagnose AL amyloidosis at a presymptomatic stage, checking biomarkers of amyloid organ involvement in patients with monoclonal gammopathies at higher risk to develop the disease. Adequate technology and expertise are needed for a prompt and correct diagnosis, particularly for ruling out non-AL amyloidoses that are now also treatable. Therapy should be carefully tailored based on severity of organ involvement and clonal characteristics, and early and continual monitoring of response is critical. Three recent randomized clinical trials moved AL amyloidosis to evidence-based era. Above all, the daratumumab-bortezomib combination is a new standard-of-care for newly diagnosed patients, inducing rapid and deep responses that translate into high rates of organ response. The availability of new effective drugs allows to better personalize the therapy, reduce toxicity, and improve outcomes. Patients should be treated within clinical trials whenever possible., (© 2022 by The American Society of Hematology.)

Cardiac amyloidosis is a systemic disease characterized by continuous deposition of misfolded proteins called amyloid fibrils in the extracellular space which result in restrictive cardiomyopathy. The most common form of cardiac amyloidosis is light chain (AL) cardiac amyloidosis, a result of continuous deposition of misfolded monoclonal immunoglobulin light chains. Transthyretin-related cardiac amyloidosis (ATTR) results from a point mutation in the transthyretin gene in an autosomal dominant fashion and presents phenotypically similar to AL cardiac amyloidosis. Cardiac amyloidosis is being increasingly recognized due to the advancements in diagnostic cardiac imaging and pharmacotherapy. Clinicians should maintain a high index of suspicion among patients with unexplained diastolic heart failure because earlier diagnosis will allow for the implementation of disease-altering therapy. With established targeted drug therapies and further breakthroughs in immunotherapy, the potential impact of diagnostic and therapeutic advancements on morbidity and mortality of patients with cardiac amyloidosis is promising., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Cardiac amyloidosis is an emerging and important cause of heart failure, arrhythmia, and other cardiovascular disease in Canada. In this context, many centres have expressed interest in the development of effective care pathways for screening, evaluating, and treating this rapidly growing patient population. In October 2019, a group of Canadian stakeholders met, including specialists in cardiac amyloidosis, experts in heart failure and chronic disease management, and academic and community-based cardiologists at various stages of cardiac amyloidosis clinic development. Objectives of the meetings included discussion of existing care pathways, consideration of barriers to program development, and achieving a consensus on essential and desirable components of a best-practice cardiac amyloidosis program. Topics discussed included optimal settings for cardiac amyloidosis clinics and integration with other specialty clinics, funding limitations that act as barriers to program development and potential solutions to these barriers, the roles of the multidisciplinary team and specialist physicians in amyloidosis care, and diagnostic pathways and strategies for the identification of patients with cardiac amyloidosis. In this report, we summarize the discussion points and key recommendations for the development of a cardiac amyloidosis clinic that emerged from this meeting, focused on program integration and care coordination, human resource elements, access to care, and quality improvement and outcome measures in cardiac amyloidosis., (Copyright © 2021 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Systemic amyloidosis encompasses a variety of diseases characterized by extracellular deposition of protein-derived fibrils in different tissues and organs. Immunoglobulin light-chain (AL) and transthyretin (ATTR) amyloid are the two types that more commonly affect the heart and in both subtypes cardiac involvement is the main determinant of prognosis. Recently, several studies have suggested that Cardiac Amyloidosis (CA) and Aortic Stenosis (AS) can coexist more frequently than previously suspected with prevalence ranging from 5,6% to 16% in different cohorts. The unexpected high prevalence of CA in AS and the availability of potentially effective treatment in CA should push us to carefully investigate elderly patients with aortic valve stenosis in order to identify those with coexistent amyloidosis. While the motivation to exclude amyloidosis was in the past their exclusion from active treatment of the valve disease, judged as futile because of their poor unavoidable prognosis, the improved therapeutic options available challenges this conservative approach. Aim of this review is to identify the triggers to investigate AS patients at risk of having concomitant ATTR-CA, to propose a diagnostic path to reach diagnosis and to discuss the changes in the therapeutic strategy caused by this discovery in the era of TAVR and active pharmacological treatments to slow down disease progression., Competing Interests: Declaration of competing interest None declared., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Amyloidoses are life-threatening diseases caused by the deposition of various proteins including apolipoprotein A-I, the major protein of plasma high-density lipoprotein. Timely diagnostics of amyloidoses are crucial for their treatment. Colombat et al. reported novel aspects of the hereditary apolipoprotein A-I amyloidosis, including its unexpected clinical presentation and genetic origins, as well as life- and vision-saving hepatorenal transplantation. This study improves the diagnostics of apolipoprotein A-I amyloidosis, optimizes its treatment, and expands our understanding of the molecular basis of this multipronged disease., (Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Cardiac amyloidosis is a potentially deadly disease characterized by progressive infiltration of amyloid fibrils, and it is increasingly recognized as an underdiagnosed but important cause of heart failure. Given its unique pathogenesis, there are key differences in the management of cardiac amyloidosis compared with other forms of heart failure. Moreover, the 2 common forms of cardiac amyloidosis, transthyretin and light-chain amyloidosis, are distinct entities with varying clinical manifestations and prognoses, leading to the need for tailored approaches to management. In the past decade, there have been many significant advances in the diagnosis and treatment of both forms of cardiac amyloidosis. For example, in selected cases, transthyretin cardiac amyloidosis can be diagnosed noninvasively with the use of bone scintigraphy imaging, avoiding the need for a biopsy. Effective, more targeted therapies have been developed for both transthyretin and light-chain amyloidosis. However, these treatments are much more effective in early stages of disease before significant end-organ amyloid deposition has occurred. Consequently, it is increasingly imperative that clinicians aggressively screen at-risk groups, identify early signs of disease, and initiate treatment. Finally, once thought to be ill advised, heart transplantation should be considered in carefully selected patients with end-stage cardiac amyloidosis, because transplant outcomes in these patients is now similar to other those for other cardiomyopathies. Given these and other recent changes in clinical practice, this article discusses several key considerations for the clinical care of patients with cardiac amyloidosis., (Copyright © 2019 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Recent developments in cardiac amyloidosis have raised awareness of the disease and have advanced diagnostic and treatment strategies. Novel therapies may vastly improve the prognosis of the disease but will be associated with significant costs. Data are needed to inform clinical decisions and to drive resource allocation within the health care system. Many aspects of disease management are unlikely to be addressed by clinical trials and are better suited to nonrandomized cohort studies, but the limited numbers of patients in any single centre present barriers to high-quality observational research. Disease registries offer opportunities to assemble large numbers of patients from multiple institutions for adequately powered observational studies, to recruit patients for randomized clinical trials; to provide real-world effectiveness and safety data, to study cost-effectiveness of novel therapies, and to engage patients in the collection of patient-reported outcome data. Existing amyloidosis registries have limitations. Canada is an ideal setting for a national amyloidosis registry, with ethnic diversity, relatively few academic centres, access to advanced diagnostic and therapeutic options, and a track record of collaboration among institutions. The Canadian Registry for Amyloidosis Research aims to capitalize on this opportunity and provide high-quality data to inform clinical practice and health care policy in Canada and beyond., (Copyright © 2020 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

The systemic amyloidoses are a group of diseases characterized by the deposition of amyloid, a material formed from misfolding of proteins, in one or more organs. The 2 commonest forms of amyloidosis are transthyretin amyloidosis (ATTR), derived from wild-type or mutant transthyretin, and light-chain (AL) amyloidosis, derived from abnormal circulating light chains produced by plasma cell dyscrasia. Both frequently involve the heart, producing an infiltrative cardiomyopathy with restrictive pathophysiology. Although advances in echocardiographic, magnetic resonance, and nuclear imaging have rendered diagnosis of cardiac amyloidosis easier, diagnosis is still often delayed. This review focuses on noncardiac manifestations of AL and TTR amyloidosis that may aid the cardiologist in making an earlier diagnosis of cardiac amyloidosis in a patient with cardiac symptoms (such as periorbital purpura in AL amyloidosis and a history of carpal tunnel syndrome and ruptured biceps tendon in ATTR). It also focuses on the unique challenges that treatment of cardiac amyloidosis poses owing to concomitant noncardiac disease, such as nephrotic syndrome-related edema and hypotension due to autonomic neuropathy, and stresses the importance of a precise typing of amyloidosis and a multidisciplinary approach to therapy., (Copyright © 2020 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Cardiac amyloidosis is an under-recognized and potentially fatal cause of heart failure and other cardiovascular manifestations. It is caused by deposition of misfolded precursor proteins as fibrillary amyloid deposits in cardiac tissues. The two primary subtypes of systemic amyloidosis causing cardiac involvement are immunoglobulin light chain (AL), a plasma cell dyscrasia, and transthyretin (ATTR), itself subdivided into a hereditary subtype caused by a gene mutation of the ATTR protein, and an age-related wild type, which occurs in the absence of a gene mutation. Clinical recognition requires a high index of suspicion, inclusive of the extracardiac manifestations of both subtypes. Diagnostic workup includes screening for serum and/or urine monoclonal protein suggestive of immunoglobulin light chains, along with serum cardiac biomarker measurement and performance of cardiac imaging for findings consistent with amyloid infiltration. Modern cardiac imaging techniques, including the use of nuclear scintigraphy with bone-seeking radiotracer to noninvasively diagnose ATTR cardiac amyloidosis, have reduced reliance on the gold standard endomyocardial biopsy. Disease-modifying therapeutic approaches have evolved significantly, particularly for ATTR, and pharmacologic therapies that slow or halt disease progression are becoming available. This Canadian Cardiovascular Society/Canadian Heart Failure Society joint position statement provides evidence-based recommendations that support the early recognition and optimal diagnostic approach and management strategies for patients with cardiac amyloidosis. This includes recommendations for the symptomatic management of heart failure and other cardiovascular complications such as arrhythmia, risk stratification, follow-up surveillance, use of ATTR disease-modifying therapies, and optimal clinical care settings for patients with this complex multisystem disease., (Copyright © 2020 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

We present a case of multiple myeloma with primary systemic amyloidosis presenting with digestive symptoms in a 32-year-old male. Initial symptoms included upper abdominal discomfort for 4 months, and stool with mucous and blood for 1 month. Erosive gastritis, Helicobacter pylori infection, haematochezia, and weight loss were noted, but without bone pain, anaemia, or hypercalcaemia. Bone marrow examination showed 18.5% mature monoclonal plasma cells that were λ light chain protein and CD38 positive. Three courses of 28-day PTD therapy (i.e., bortezomib, dexamethasone, and thalidomide) were administered. Gastrointestinal symptoms and laboratory parameters improved. Post-treatment follow-up showed 0.5% plasma cells with normal morphology in bone marrow, urine λ light chain 10.1 mg/L, and negative M protein. Nevertheless, the patient died of multiple organ system failure 8 months after treatment. CONCLUSIONS: Amyloidosis is an uncommon finding in patients with multiple myeloma, especially in younger individuals., (Copyright © 2020 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.)

Background: Differential diagnosis of genetic causes of left ventricular hypertrophy (LVH) is crucial for disease-specific therapy. We aim to describe the prevalence of Cardiac Amyloidosis (CA) among patients ≥40 years with an initial diagnosis of HCM referred for second opinion to national cardiomyopathy centres., Methods: Consecutive patients aged ≥40 years referred with a tentative HCM diagnosis in the period 2014-2017 underwent clinical evaluation and genetic testing for HCM (including trans-thyretin-TTR). Patients with at least one red flag for CA underwent blood/urine tests, abdominal fat biopsy and/or bone-scintigraphy tracing and eventually ApoAI sequencing., Results: Out of 343 patients (age 60 ± 13 years), 251 (73%) carried a likely/pathogenic gene variant, including 12 (3.5%) in the CA-associated genes TTR (n = 11) and ApoAI (n = 1). Furthermore, 6 (2%) patients had a mutation in GLA. Among the remaining, mutation-negative patients, 26 with ≥1 CA red-flag were investigated further: 3 AL-CA and 17 wild-type-TTR-CA were identified. Ultimately, 32(9%) patients were diagnosed with CA. Prevalence of CA increased with age: 1/75 (1%) at age 40-49, 2/86 (2%) at age 50-59, 8/84 (9%) at age 60-69, 13/61 (21%) at age 70-79, 8/31 (26%) at age ≥80 (p for trend <0.01)., Conclusions: Among patients referred with and initial diagnosis of HCM, CA was the most common unrecognized mimic (9% prevalence) and increased with age (from 1% at ages 40-49 years to 26% >80 years). Age at diagnosis should be considered one of the most relevant red flags for CA in patients with HCM phenotypes; however, there is no clear age cut-off mandating scintigraphy and other second level investigations in the absence of other features suggestive of CA., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Interstitial heart disease, whether primarily from myocardial fibrosis or cardiac amyloidosis, indicates excess protein accumulation in the interstitium and constitutes a major source of heart failure with excess cardiac morbidity and mortality. Myocardial fibrosis (defined as excess myocardial collagen concentration that distorts myocardial architecture) is prevalent and causes cardiac symptoms and ultimately adverse cardiac events, such as heart failure, arrhythmia, and death. Conversely, cardiac amyloidosis is far less prevalent than myocardial fibrosis but represents a more extreme form of interstitial heart disease with marked interstitial expansion, profound architectural distortion, and then rapid clinical decline. Myocardial extracellular volume measures fundamentally advance the understanding of myocardium and specifically highlights the role of the interstitium. Rather than conceptualizing myocardium as a homogenous tissue, dichotomizing the myocardium into its interstitial (including the microvasculature) and cardiomyocyte phenotypes promotes additional understanding of heart failure pathophysiology that may spur the development of more effective therapies., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Light chain amyloidosis is a deadly disease in which a monoclonal plasma cell dyscrasia produces misfolded immunoglobulin light chains (AL) that aggregate and form rigid amyloid fibrils. The amyloid deposits infiltrate one or more organs, leading to injury and severe dysfunction. The degree of cardiac involvement is a major driver of morbidity and mortality. Early diagnosis and treatment are crucial to prevent irreversible end-organ damage and improve overall survival. Treatment of AL cardiac amyloidosis involves eliminating the underlying plasma cell dyscrasia with chemotherapy and pursuing supportive heart failure management., (Copyright © 2019 Elsevier Inc. All rights reserved.)

This study sought to retrospectively investigate the outcomes of patients with light-chain amyloidosis (AL) with advanced cardiac involvement who were treated with a strategy of heart transplantation (HT) followed by delayed autologous stem cell transplantation (ASCT) at 1-year posttransplant. Patients with AL amyloidosis with substantial cardiac involvement have traditionally had very poor survival (eg, several months). A few select centers have reported their outcomes for HT followed by a strategy of early ASCT (ie, 6 months) for CA. The outcomes of patients undergoing a delayed strategy have not been reported. All patients with AL amyloidosis at a single institution undergoing evaluation for HT from 2004-2018 were included. Retrospective analyses were performed. Sixteen patients underwent HT (including two combined heart-kidney transplant) for AL amyloidosis. ASCT was performed in a total of nine patients to date at a median 13.5 months (12.8-32.9 months) post-HT. Survival was 87.5% at 1 year and 76.6% at 5 years, comparable to institutional outcomes for nonamyloid HT recipients. In addition to these 16 patients, two patients underwent combined heart-lung transplantation. A strategy of delayed ASCT 1-year post-HT for patients with AL amyloidosis is feasible, safe, and associated with comparable outcomes to those undergoing an earlier ASCT strategy., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Carpal tunnel syndrome (CTS) can be caused by the deposition and accumulation of misfolded proteins called amyloid and is often an early manifestation of systemic amyloidosis. In patients undergoing surgery for idiopathic CTS, a recent study identified amyloidosis by tenosynovial biopsy in 10.2% of men older than 50 years and women older than 60 years; all positive patients had bilateral symptoms. These findings have led to a renewed interest in amyloidosis as an etiology of CTS. The 2 most common systemic amyloidoses, immunoglobulin light chain and transthyretin amyloidosis, affect the heart, nerves, and other organ systems throughout the body including the soft tissues. Patients with cardiac involvement of amyloidosis have an especially poor prognosis if the disease remains unrecognized and untreated. Early diagnosis is paramount, and patients classically present with cardiac disease several years after being operated on by a hand surgeon for carpal tunnel release. Herein, we present a review of amyloidosis as it pertains to CTS and an algorithm for the detection of amyloidosis in patients undergoing carpal tunnel release. Implementation of this straightforward algorithm will allow for early diagnosis of amyloidosis, a group of progressive and lethal diseases., (Copyright © 2019 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Immunoglobulin light-chain (AL) amyloidosis is a rare life-threatening disease caused by light chains that are toxic to vital organs such as the heart, kidneys, liver and peripheral nervous system, and that misfold and assemble as amyloid fibrils and deposit both in affected organs and systemically in the vasculature and other tissues. Patients afflicted by this disease have B-cell disorders, almost always related to clonal plasma cells in the bone marrow, the burden of which can range from small clones involving 5% or less of marrow cells to frank multiple myeloma. The goal of therapy is to eliminate the clonal plasma cells producing these toxic light chains to halt and possibly reverse symptomatic organ damage. While autologous stem cell transplantation can be a very effective treatment modality in AL, it has a limited role due to the frailty of this particular population. Conservative treatment in the form of chemotherapy has become the backbone of therapy. Bortezomib combined with alkylators has proven quite successful in inducing hematologic responses. However, despite these advances, tolerability and resistance continue to be an ongoing issue. Novel anti-plasma cell therapies such as ixazomib, carfilzomib, lenalidomide and pomalidomide are actively being combined and evaluated in clinical trials for efficacy and toxicity in this challenging patient population. Other approaches, such as monoclonal antibodies targeting surface proteins and amyloid deposits, are being tested and combined with novel agents. In this review, we will provide an overview of the clinical trials that have led to current treatment algorithms and will also discuss monoclonal antibodies currently under investigation and in various stages of clinical development., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Pulmonary localization of B-cell lymphoma associated with deposits of amyloid material is a rare finding in the thoracic disease spectrum. This report describes a rare case of nodular pulmonary amyloidosis in a 50-year-old patient. He underwent left upper lobectomy for mucosa-associated lymphoid tissue lymphoma that originated from bronchial lymphoid tissue., (Copyright © 2019 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Lysozyme amyloidosis is a non-neuropathic hereditary amyloidosis identified in 1993. About fifty cases of this rare, probably under-diagnosed disease are reported. Lysozyme amyloidosis has a very broad spectrum of clinical manifestations. Sicca syndrome is often the first symptom, preceding the diagnosis by several years. Every part of the digestive tract can be involved with different grades of severity. The hallmark of this amyloidosis is the usually life-threatening spontaneous hepatic rupture. Renal involvement is frequent and progresses towards end-stage renal failure and dialysis. Skin, lymph nodes, and spleen can also be affected. More recently, cardiac and pulmonary involvement was reported. Phenotypic heterogeneity and incomplete penetrance make the clinical diagnosis difficult. Amyloid deposits are revealed by Congo red staining with birefringence under polarized light. They can be limited or diffuse and lead to the progressive destruction of the architecture of an organ and its failure. Immunohistochemistry reveals the nature of the amyloid variant by identifying antilysozyme antibodies in the deposit. Up to know, eight pathologic mutations and one polymorphism involving exons 2, 3, and 4 of the lysozyme gene have been identified. The transmission is autosomal dominant, without any genotype-phenotype correlation. The therapeutic options are limited and based on symptomatic or supportive treatment. Renal and hepatic transplant has proved its benefits with a prolonged graft survival. A long term regular and multidisciplinary follow-up is required., (Copyright © 2018 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

Case Presentation: A 45-year-old woman presented for evaluation for 3 months of coughing and dyspnea. A recent chest CT scan done for workup of her symptoms revealed a 2-cm right-sided pulmonary nodule. She had a medical history of Sjögren syndrome, hypertension, and obesity. She also noted a weight loss of 30 lb over the last 3 years. She denied smoking, alcohol consumption, illicit drug use, or occupational exposures. A chest radiograph done 3 years prior did not reveal any pulmonary nodules. She had no personal or family history of arteriovenous malformations, hamartomas, or any malignancies and had been up to date with her breast cancer screening. She was treated with courses of hydroxychloroquine and mycophenolate mofetil for her Sjögren syndrome and did not have a history of opportunistic pulmonary infections. She denied any recent travel or exposure to TB., (Copyright © 2018 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Two categories of renal disorders associated with monoclonal gammopathies are to be distinguished, according to the characteristics of the underlying B-cell clone. The first group of renal diseases always occurs in the setting of high tumor mass with production of large amounts of monoclonal immunoglobulins. The main complication is the so-called myeloma cast nephropathy, which almost invariably complicates high tumor mass myeloma. The second group includes all renal disorders caused by a monoclonal immunoglobulin secreted by a nonmalignant B-cell clone, and currently referred as a "monoclonal gammopathy of renal significance (MGRS)". This term was introduced to distinguish monoclonal gammopathies that are responsible for the development of kidney damage from those that are truly benign. The spectrum of renal diseases in MGRS is wide and its classification relies on the localization of renal lesions, either glomerular or tubular, and on the pattern of ultrastructural organization of immunoglobulin deposits. Physicochemical characteristics of the pathogenic monoclonal immunoglobulin are probably involved in their propensity to deposit or precipitate in the kidney, as illustrated by the high rate of recurrence of each specific type after kidney transplantation. Early diagnosis and efficient chemotherapy targeting the causal B-cell clone are mandatory to improve renal prognosis and patient survival., (Copyright © 2017 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

Among patients with immunoglobulin light chain (AL) amyloidosis, there is little consensus on when reinstitution of chemotherapy should occur. We conducted a retrospective study to evaluate the patterns of relapse or progression (R/P) and the timing of reinitiating therapy among 235 patients initially treated with autologous stem cell transplant (ASCT) at Mayo Clinic. The median time from ASCT to second-line therapy was 24.3 months. At the time of restarting therapy, median difference of free light chain (dFLC) was 9.9 mg/dL (42% of diagnosis value), 32% had a dFLC <5 mg/dL, and 63% met criteria for organ R/P. The indications for retreatment were (1) clinical suspicion of R/P, 10%; 92) hematologic R/P only, 23%; (3) organ R/P only, 32%; (4) both hematologic and organ R/P, 31%; and (5) suboptimal response to ASCT and second-line therapy as consolidation, 4%. Patients with organ progression at the time of second-line therapy had inferior survival. Although a dFLC of >5 mg/dL at the time of reinstituting therapy was associated with risk, patients relapsing from very good partial response (VGPR) or better had a longer time to develop organ progression after hematologic R/P (24.2 vs 3.2 months, P = .007). These data suggest that the best candidates for clinical trials testing novel plasma cell-directed chemotherapy beyond first line may be those patients who are either relapsing from VGPR or better (dFLC at diagnosis was >5 mg/dL) or having inadequate response to prior therapy. This strategy should allow for hematologic response assessment while avoiding the risk of deleterious organ progression. Implementation of more stringent progression criteria may also be warranted., (© 2017 by The American Society of Hematology.)

Since the identification of a valine-to-isoleucine substitution at position 122 (TTR V122I; pV142I) in the transthyretin (TTR)-derived fibrils extracted from the heart of a patient with late-onset cardiac amyloidosis, it has become clear that the amyloidogenic mutation and the disease occur almost exclusively in individuals of identifiable African descent. In the United States, the amyloidogenic allele frequency is 0.0173 and is carried by 3.5% of community-dwelling African Americans. Genotyping across Africa indicates that the origin of the allele is in the West African countries that were the major source of the slave trade to North America. At autopsy, the allele was found to be associated with cardiac TTR amyloid deposition in all the carriers after age 65 years; however, the clinical penetrance varies, resulting in substantial heart disease in some carriers and few symptoms in others. The allele has been found in 10% of African Americans older than age 65 with severe congestive heart failure. At this time there are potential forms of therapy in clinical trials. The combination of a highly accurate genetic test and the potential for specific therapy demands a greater awareness of this autosomal dominant, age-dependent cardiac disease in the cardiology community.Genet Med advance online publication 19 January 2017.

In light of major advances in immunoglobulin light chain (AL) amyloidosis, we evaluated the trends in presentation, management, and outcome among 1551 newly diagnosed AL amyloidosis patients seen in our institution from 2000 to 2014. As compared with the 2 intervals 2000-2004 and 2005-2009, patients diagnosed in 2010-2014 were less likely to have >2 involved organs. Utilization of autologous stem cell transplant (ASCT) was similar across all periods, about one-third of patients, but there was an increase in the use of pre-ASCT bortezomib induction and of unattenuated melphalan conditioning in 2010-2014 compared with earlier periods. Non-ASCT first-line regimen changed with 65% of patients in 2010-2014 received bortezomib-based therapy, 79% of patients in 2005-2009 received melphalan-dexamethasone, and 64% of patients in 2000-2004 received melphalan-prednisone. The rate of better than very good partial response (VGPR) was higher in more recent periods (66% vs 58% vs 51%; P = .001), a change largely driven by improved VGPR rates in the non-ASCT population. Overall survival (OS) has improved, with inflection points for improvement differing for the ASCT and non-ASCT groups. In the ASCT population, the greatest gains were after 2010 (4-year OS, 91% compared with 73% and 65%). In the non-ASCT group, greatest gains were after 2005 (4-year OS, 38%, 32%, and 16%). Fewer patients died within 6 months of diagnosis in the 2 later periods (24% vs 25% vs 37%; P < .001). Overall, outcomes among patients with AL amyloidosis have improved with earlier diagnosis, higher rates of VGPR, lower early mortality, and improved OS., (© 2017 by The American Society of Hematology.)

Objectives: The aim of this study was to access the prognostic implication of late gadolinium enhancement (LGE) in patients with systemic amyloidosis undergoing cardiac magnetic resonance (CMR)., Background: Cardiac amyloidosis confers significantly worse prognosis in patients with systemic amyloidosis. CMR imaging has emerged as an attractive noninvasive modality to diagnose cardiac involvement in patients with systemic amyloidosis. We performed a systemic review and meta-analysis to evaluate the prognostic role of LGE-CMR imaging in patients with systemic amyloidosis., Methods: Electronic databases MEDLINE, PubMed, Embase, and Cochrane were systematically searched to identify studies evaluating the association between LGE-CMR and prognosis in systemic amyloidosis with cardiac involvement. The present study was designed to systematically review and assess the association between LGE and the primary endpoint of all-cause mortality. A random effects model was used to calculate a pooled odds ratio using inverse-variance weighting., Results: Data were included from 7 studies with a total of 425 patients and a mean follow-up of 25 months. Patients had a weighted average age of 64 years and left ventricular ejection fraction of 59.2%; 67% were male. Endomyocardial biopsy was positive for amyloidosis in 20%, whereas LGE was present in 73% of patients. LGE-positive patients had increased overall mortality compared with those without LGE (pooled odds ratio: 4.96; 95% confidence interval [CI]: 1.90 to 12.93; p = 0.001). For the LGE group, the pooled death rate was 0.07 (95% CI: 0.03 to 0.19) events per year and for the LGE+ group, the rate was 0.25 (95% CI: 0.16 to 0.39 per year; p = 0.001). The proportion of patients with cardiac biopsy within each study ranged from 3% to 68%, and the relationship between LGE status and death did not vary according to cardiac biopsy proportion across studies., Conclusions: LGE on CMR in patients with systemic amyloidosis with known or suspected cardiac amyloidosis is associated with increased risk of all-cause mortality., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Cardiac amyloidosis (CA) is associated with a poor prognosis with the proposed mechanism of sudden cardiac death in the majority of patients being pulseless electrical activity. However, the incidence of ventricular arrhythmias (VA) and implantable cardioverter-defibrillator (ICD) indications in CA patients are unclear. We performed a detailed evaluation of our CA population undergoing ICD implantation and assessed appropriate ICD therapy and survival predictors., Methods: We included consecutive patients from June 2008 to November 2014 in five centers. ICDs were systematically interrogated and clinical data recorded during follow-up., Results: Forty-five patients (35 males, mean age 66±12years) with CA who underwent ICD implantation (84.4% primary prevention) were included. CA types were hereditary transthyretin in 27 patients (60%), light chain (AL) in 12 (27%) and senile in 6 (13%). After a mean follow-up of 17±14months, 12 patients (27%) had at least 1 appropriate ICD therapy occurring after 4.7±6.6months. Patients with or without ICD therapy had no significant differences in baseline characteristics, amyloidosis type, LVEF, and type of prevention although there was a trend towards a better 2D global longitudinal strain in patients with ICD therapy (P=0.08). Over the follow-up, 12 patients died (27%) and 6 underwent cardiac transplantation (13%). From multivariate analysis a worse prognosis was associated with higher NT-proBNP level (>6800pg/mL, HR=5.5[1.7-17.8]) and AL type (HR=4.9[1.5-16.3])., Conclusions: Appropriate ICD therapies are common (27%) in CA patients. No specific strong VA predictor could be identified. However, patients with advanced heart disease, especially with AL-CA, display a poorer outcome., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Amyloidosis is mainly a systemic disease belonging to protein-folding diseases. The past 10 years have shown significant progress in typing and the clinical management of amyloidosis, in the identification of novel prognostic markers for risk-stratification, and also in the development of new therapeutic agents. Biological molecular techniques are now able to type amyloidosis which were unidentified. Cardiac MRI and biomarkers allow a precise risk-stratification, especially in AL amyloidosis. If necessary, this prognostic evaluation may lead to rapid changes in the chemotherapy treatment. Emerging treatments rely on biotherapies, gene therapy, immunotherapy and blocking analogous agents. They give hope about an increase of survival of patients with systemic amyloidosis., (Copyright © 2016 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

Cytogenetic aberrations detected by interphase fluorescence in situ hybridization (iFISH) of plasma cells are routinely evaluated as prognostic markers in multiple myeloma. This long-term follow-up study aimed to assess the prognosis of systemic light chain amyloidosis (AL) patients treated with high-dose melphalan (HDM) chemotherapy and autologous stem cell transplantation, depending on iFISH results. Therefore, we analyzed a consecutive cohort of 123 AL patients recruited from 2003 to 2014. HDM was safe, with only 1 of 123 patients dying as a result of treatment-related mortality, and effective, with a complete remission (CR) rate of 34%. Translocation t(11;14) as the most prevalent aberration (59%) led to an improved CR rate after high-dose therapy (41.2% vs 20.0%; P = .02), translating into a prolonged hematologic event-free survival (hemEFS; median, 46.1 vs 28.1 months; P = .05) and a trend for better overall survival (median, not reached vs 93.7 months; P = .07). In multivariate analysis, t(11;14) was confirmed as a favorable prognostic factor regarding hemEFS along with lower values for the difference between involved and uninvolved free light chains. Conversely, deletion 13q14, gain of 1q21, and hyperdiploidy had no significant prognostic impact. The high-risk cytogenetic aberrations t(4;14), t(14;16), and del(17p13) conferred an unfavorable prognosis, although statistical significance was reached only for univariate CR analysis in this small group of 9 patients. Thus, t(11;14) positivity in HDM-treated AL patients conferred superior CR rates and hemEFS. In view of the reduced response of t(11;14) to bortezomib, this highlights the impact of therapy on the prognostic role of cytogenetic aberrations., (© 2016 by The American Society of Hematology.)

Light chain (AL) amyloidosis is caused by a usually small plasma cell clone producing a misfolded light chain that deposits in tissues. Survival is mostly determined by the severity of heart involvement. Recent studies are clarifying the mechanisms of cardiac damage, pointing to a toxic effect of amyloidogenic light chains and offering new potential therapeutic targets. The diagnosis requires adequate technology, available at referral centers, for amyloid typing. Late diagnosis results in approximately 30% of patients presenting with advanced, irreversible organ involvement and dying in a few months despite modern treatments. The availability of accurate biomarkers of clonal and organ disease is reshaping the approach to patients with AL amyloidosis. Screening of early organ damage based on biomarkers can help identify patients with monoclonal gammopathy of undetermined significance who are developing AL amyloidosis before they become symptomatic. Staging systems and response assessment based on biomarkers facilitate the design and conduction of clinical trials, guide the therapeutic strategy, and allow the timely identification of refractory patients to be switched to rescue therapy. Treatment should be risk-adapted. Recent studies are linking specific characteristics of the plasma cell clone to response to different types of treatment, moving toward patient-tailored therapy. In addition, novel anti-amyloid treatments are being developed that might be combined with anti-plasma cell chemotherapy., (© 2016 by The American Society of Hematology.)

Tissue deposition of protein fibrils causes a group of rare diseases called systemic amyloidoses. This Seminar focuses on changes in their epidemiology, the current approach to diagnosis, and advances in treatment. Systemic light chain (AL) amyloidosis is the most common of these conditions, but wild-type transthyretin cardiac amyloidosis (ATTRwt) is increasingly being diagnosed. Typing of amyloid fibrils, a critical determinant of therapy, has improved with the wide availability of laser capture and mass spectrometry from fixed histological tissue sections. Specific and accurate evaluation of cardiac amyloidosis is now possible using cardiac magnetic resonance imaging and cardiac repurposing of bone scintigraphy tracers. Survival in AL amyloidosis has improved markedly as novel chemotherapy agents have become available, but challenges remain in advanced disease. Early diagnosis, a key to better outcomes, still remains elusive. Broadening the amyloid-specific therapeutic landscape to include RNA inhibitors, fibril formation stabilisers and inhibitors, and immunotherapeutic targeting of amyloid deposits holds promise to transform outcomes in systemic amyloidoses., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Monoclonal immunoglobulin M (IgM)-related light chain (AL) amyloidosis, which accounts for 5%-7% of all AL amyloidosis cases, is a distinct clinical entity that poses specific challenges to clinicians. Several studies reported that although there is a substantial overlap, the pattern of organ involvement is peculiar, with higher frequencies of lung, lymph nodes, and peripheral nervous system involvement. A recent collaborative study from three European referral centers, defined that cardiac involvement, advanced Mayo disease stage, neuropathic, and liver involvement were independent factors that had impact on survival in IgM-AL amyloidosis patients. Once the diagnosis of amyloidosis is made, correct amyloid typing is necessary to design appropriate therapy and follow-up. Treatment is focused on the suppression of the clone, and fast reduction of the circulating free light chains. New drugs targeting the amyloid deposits will be used in combination with anti-clone therapies., (Copyright © 2016. Published by Elsevier Ltd.)

Systemic immunoglobulin light chain (LC) amyloidosis (AL) is a potentially fatal disease caused by immunoglobulin LC produced by clonal plasma cells. These LC form both toxic oligomers and amyloid deposits disrupting vital organ function. Despite reduction of LC by chemotherapy, the restoration of organ function is highly variable and often incomplete. Organ damage remains the major source of mortality and morbidity in AL. This review focuses on the challenges posed by emerging therapies that may limit the toxicity of LC and improve organ function by accelerating the resorption of amyloid deposits., (© 2016 by The American Society of Hematology.)