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European Heart Journal Apr 2021Cardiac amyloidosis is a serious and progressive infiltrative disease that is caused by the deposition of amyloid fibrils at the cardiac level. It can be due to rare...
Cardiac amyloidosis is a serious and progressive infiltrative disease that is caused by the deposition of amyloid fibrils at the cardiac level. It can be due to rare genetic variants in the hereditary forms or as a consequence of acquired conditions. Thanks to advances in imaging techniques and the possibility of achieving a non-invasive diagnosis, we now know that cardiac amyloidosis is a more frequent disease than traditionally considered. In this position paper the Working Group on Myocardial and Pericardial Disease proposes an invasive and non-invasive definition of cardiac amyloidosis, addresses clinical scenarios and situations to suspect the condition and proposes a diagnostic algorithm to aid diagnosis. Furthermore, we also review how to monitor and treat cardiac amyloidosis, in an attempt to bridge the gap between the latest advances in the field and clinical practice.
Topics: Amyloidosis; Cardiomyopathies; Heart; Heart Diseases; Humans; Myocardium
PubMed: 33825853
DOI: 10.1093/eurheartj/ehab072 -
Acta Haematologica 2020Amyloidosis is a group of complex diseases caused by extracellular deposition of pathological insoluble fibrillary protein in organs and tissues and may result in severe... (Review)
Review
Amyloidosis is a group of complex diseases caused by extracellular deposition of pathological insoluble fibrillary protein in organs and tissues and may result in severe organ dysfunction. Despite the etiological heterogeneity of systemic amyloidosis, the clinical manifestations of the different forms of amyloidosis largely overlap and depend upon the effected organ. The signs and symptoms that should raise suspicion for the potential diagnosis of amyloidosis are usually nonspecific; therefore, establishing the diagnosis is difficult, and early diagnosis requires clinical suspicion. Light chain (AL) amyloidosis may present with highly specific signs such as macroglossia and periorbital purpura, but these signs are insensitive. Amyloidosis is still underdiagnosed, even though treatments are now available and are effective in improving patient's survival and quality of life. Cardiac amyloidosis is the major determinant of survival, and the earlier it is detected the better the survival. All MGUS patients should be routinely screened for AL amyloidosis by a focused history and physical examination and routine assessment of urine albumin. The aim of this review is to provide clinicians with knowledge about the signs and symptoms that raise the suspicion of amyloidosis, bearing in mind the importance of early diagnosis of this disease.
Topics: Amyloidosis; Animals; Diagnosis, Differential; Disease Susceptibility; Humans; Immunoglobulin Light-chain Amyloidosis; Male; Middle Aged; Organ Specificity; Phenotype
PubMed: 32340017
DOI: 10.1159/000506617 -
Journal of Internal Medicine Mar 2021Systemic amyloidosis is a rare protein misfolding and deposition disorder leading to progressive organ failure. There are over 15 types of systemic amyloidosis, each... (Review)
Review
Systemic amyloidosis is a rare protein misfolding and deposition disorder leading to progressive organ failure. There are over 15 types of systemic amyloidosis, each caused by a different precursor protein which promotes amyloid formation and tissue deposition. Amyloidosis can be acquired or hereditary and can affect various organs, including the heart, kidneys, liver, nerves, gastrointestinal tract, lungs, muscles, skin and soft tissues. Symptoms are usually insidious and nonspecific resulting in diagnostic delay. The field of amyloidosis has seen significant improvements over the past decade in diagnostic accuracy, prognosis prediction and management. The advent of mass spectrometry-based shotgun proteomics has revolutionized amyloid typing and has led to the discovery of new amyloid types. Accurate typing of the precursor protein is of paramount importance as the type dictates a specific management approach. In this article, we review each type of systemic amyloidosis to provide the practitioner with practical tools to improve diagnosis and management of these rare disorders.
Topics: Amyloidosis; Biomarkers; Diagnostic Imaging; Disease Progression; Humans; Mass Spectrometry; Prognosis; Proteomics
PubMed: 32929754
DOI: 10.1111/joim.13169 -
Journal of the American College of... Nov 2019The prevalence of calcific aortic stenosis (AS) and of cardiac amyloidosis (CA) increases with age, and their association is not uncommon in the elderly. The... (Review)
Review
The prevalence of calcific aortic stenosis (AS) and of cardiac amyloidosis (CA) increases with age, and their association is not uncommon in the elderly. The identification of CA is particularly challenging in patients with AS because these 2 conditions share several features. It is estimated that ≤15% of the AS population and ≤30% of the subset with low-flow, low-gradient pattern may have CA. In patients with AS, CA is associated with increased risk of heart failure, mortality, and treatment futility with aortic valve replacement. In case of suspicion of CA, it is thus crucial to confirm the diagnosis to guide therapeutic management of AS and eventually implement recently developed pharmacological treatment dedicated to transthyretin amyloidosis. Given the high surgical risk of patients with AS and concomitant CA, transcatheter aortic valve replacement may be preferred to surgery in these patients.
Topics: Amyloidosis; Aortic Valve; Aortic Valve Stenosis; Calcinosis; Humans; Prevalence
PubMed: 31753206
DOI: 10.1016/j.jacc.2019.09.056 -
Heart Failure Clinics Jul 2022Amyloid deposits are defined by their tinctorial properties. Under the light microscope amyloid deposits are eosinophilic and amorphous when stained with hematoxylin and... (Review)
Review
Amyloid deposits are defined by their tinctorial properties. Under the light microscope amyloid deposits are eosinophilic and amorphous when stained with hematoxylin and eosin. With Congo red staining the deposits are positive and under polarized light will exhibit green birefringence. Sixty years later electron microscopy demonstrated that all deposits were fibrillar. All amyloid deposits are protein derived. The clinical characteristics will be driven by the nature of the protein subunit. In cardiology, the 2 most common subunits accounting for well more than 90% of cardiac amyloidosis are either immunoglobulin light chain, amyloid light-chain (AL) amyloidosis, or transthyretin; transthyretin (TTR) amyloidosis. Although 70% of patients with systemic amyloidosis have cardiac involvement the diagnosis is made by cardiologists only 20% of the time, suggesting significant gaps in knowledge in how to establish a workflow to arrive at a diagnosis in everyday practice.
Topics: Amyloidosis; Humans; Plaque, Amyloid; Prealbumin
PubMed: 35718420
DOI: 10.1016/j.hfc.2022.02.005 -
Molecules (Basel, Switzerland) Feb 2022The amyloid hypothesis of Alzheimer's disease has long been the predominant theory, suggesting that Alzheimer's disease is caused by the accumulation of amyloid beta... (Review)
Review
The amyloid hypothesis of Alzheimer's disease has long been the predominant theory, suggesting that Alzheimer's disease is caused by the accumulation of amyloid beta protein (Aβ) in the brain, leading to neuronal toxicity in the central nervous system (CNS). Because of breakthroughs in molecular medicine, the amyloid pathway is thought to be central to the pathophysiology of Alzheimer's disease (AD). Currently, it is believed that altered biochemistry of the Aβ cycle remains a central biological feature of AD and is a promising target for treatment. This review provides an overview of the process of amyloid formation, explaining the transition from amyloid precursor protein to amyloid beta protein. Moreover, we also reveal the relationship between autophagy, cerebral blood flow, ACHE, expression of LRP1, and amyloidosis. In addition, we discuss the detailed pathogenesis of amyloidosis, including oxidative damage, tau protein, NFTs, and neuronal damage. Finally, we list some ways to treat AD in terms of decreasing the accumulation of Aβ in the brain.
Topics: Alzheimer Disease; Amyloid; Amyloid beta-Peptides; Amyloidosis; Animals; Autophagy; Biomarkers; Brain; Disease Management; Disease Susceptibility; Gene Expression Regulation; Humans; Plaque, Amyloid; Risk Factors
PubMed: 35209007
DOI: 10.3390/molecules27041210 -
Blood May 2022The treatment of patients with systemic light chain (AL) amyloidosis is a challenge to hematologists. Despite its generally small size, the underlying clone causes a...
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.
Topics: Amyloidosis; Bortezomib; Humans; Immunoglobulin Light-chain Amyloidosis; Immunotherapy; Paraproteinemias
PubMed: 34517412
DOI: 10.1182/blood.2020008737 -
Cardiovascular Research Feb 2023Transthyretin cardiac amyloidosis (ATTR-CA) is an increasingly recognized cause of heart failure (HF) and mortality worldwide. Advances in non-invasive diagnosis,...
Transthyretin cardiac amyloidosis (ATTR-CA) is an increasingly recognized cause of heart failure (HF) and mortality worldwide. Advances in non-invasive diagnosis, coupled with the development of effective treatments, have shifted ATTR-CA from a rare and untreatable disease to a relatively prevalent condition that clinicians should consider on a daily basis. Amyloid fibril formation results from age-related failure of homoeostatic mechanisms in wild-type ATTR (ATTRwt) amyloidosis (non-hereditary form) or destabilizing mutations in variant ATTR (ATTRv) amyloidosis (hereditary form). Longitudinal large-scale studies in the United States suggest an incidence of cardiac amyloidosis in the contemporary era of 17 per 100 000, which has increased from a previous estimate of 0.5 per 100 000, which was almost certainly due to misdiagnosis and underestimated. The presence and degree of cardiac involvement is the leading cause of mortality both in ATTRwt and ATTRv amyloidosis, and can be identified in up to 15% of patients hospitalized for HF with preserved ejection fraction. Associated features, such as carpal tunnel syndrome, can preceed by several years the development of symptomatic HF and may serve as early disease markers. Echocardiography and cardiac magnetic resonance raise suspicion of disease and might offer markers of treatment response at a myocardial level, such as extracellular volume quantification. Radionuclide scintigraphy with 'bone' tracers coupled with biochemical tests may differentiate ATTR from light chain amyloidosis. Therapies able to slow or halt ATTR-CA progression and increase survival are now available. In this evolving scenario, early disease recognition is paramount to derive the greatest benefit from treatment.
Topics: Humans; Amyloidosis; Cardiomyopathies; Echocardiography; Heart Failure; Magnetic Resonance Imaging; Prealbumin
PubMed: 35929637
DOI: 10.1093/cvr/cvac119 -
Acta Haematologica 2020Amyloidosis is a general term for diseases characterised by the deposition of insoluble amyloid fibrils in organs or tissues, leading to organ dysfunction and, in many... (Review)
Review
Amyloidosis is a general term for diseases characterised by the deposition of insoluble amyloid fibrils in organs or tissues, leading to organ dysfunction and, in many cases, death. Amyloid fibrils are derived from soluble precursor proteins, with the number of known amyloidogenic proteins increasing over time. The identity of the precursor protein often predicts the disease phenotype, although many of the amyloidoses have overlapping clinical features. Most patients with amyloidosis will require biopsy of an involved organ or tissue to confirm the diagnosis. Cardiac transthyretin amyloidosis, however, may be diagnosed without a biopsy provided stringent criteria are met. Where amyloid is confirmed histologically, the identity of the amyloidogenic protein must be determined, given several of the amyloidoses have disease-specific therapies. Laser capture microdissection and tandem mass spectrometry, LCM-MS, has revolutionised amyloid subtyping, being able to identify the amyloidogenic protein more reliably than antibody-based methods such as immunohistochemistry. Here we summarise the biopsy approach to amyloidosis, as well as the non-biopsy diagnosis of cardiac transthyretin amyloidosis. Proteomic and antibody-based methods for amyloid subtyping are reviewed. Finally, an algorithm for confirming the diagnosis of amyloidosis is presented.
Topics: Algorithms; Amyloid; Amyloidosis; Biomarkers; Biopsy; Disease Management; Disease Susceptibility; Humans; Immunohistochemistry; Mass Spectrometry; Microscopy, Fluorescence; Microscopy, Immunoelectron; Organ Specificity; Protein Aggregation, Pathological; Proteomics
PubMed: 32544917
DOI: 10.1159/000508022 -
JACC. Clinical Electrophysiology Apr 2020Cardiac amyloidosis is characterized by extracellular protein fibril deposition in the myocardium leading to restrictive heart failure. Both atrial and ventricular... (Review)
Review
Cardiac amyloidosis is characterized by extracellular protein fibril deposition in the myocardium leading to restrictive heart failure. Both atrial and ventricular arrhythmias, along with conduction disease, are common in cardiac amyloidosis, and are often highly symptomatic and poorly tolerated. Many commonly used therapeutics such as beta-blockers, calcium-channel blockers, and digoxin may be poorly tolerated and lead to clinical decompensation in this population, adding complexity to the co-management of these conditions. In addition, studies have shown that atrial fibrillation with cardiac amyloidosis carries a high risk of stroke and systemic embolism, making anticoagulation indicated in all patients regardless of CHADS-VASc score. Ventricular arrhythmias are common, whereas an implantable cardioverter-defibrillator has not been shown to improve survival. Conduction disease is also common and permanent pacemaker placement is often needed. High-quality evidence and guideline recommendations are limited with regard to the management of arrhythmias in cardiac amyloidosis. Providers are often left to clinical experience and expert consensus to aid in decision-making. In this focused review, we outline current guideline recommendations, summarize both historical and contemporary data, and describe evidence-based strategies for managing arrhythmias and their sequelae in patients with cardiac amyloidosis.
Topics: Amyloidosis; Atrial Fibrillation; Defibrillators, Implantable; Heart; Humans; Stroke
PubMed: 32327068
DOI: 10.1016/j.jacep.2020.01.004