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JACC. Cardiovascular Imaging Apr 2020This study aimed to investigate the accuracy of a broad range of echocardiographic variables to develop multiparametric scores to diagnose CA in patients with proven...
OBJECTIVES
This study aimed to investigate the accuracy of a broad range of echocardiographic variables to develop multiparametric scores to diagnose CA in patients with proven light chain (AL) amyloidosis or those with increased heart wall thickness who had amyloid was suspected. We also aimed to further characterize the structural and functional changes associated with amyloid infiltration.
BACKGROUND
Cardiac amyloidosis (CA) is a serious but increasingly treatable cause of heart failure. Diagnosis is challenging and frequently unclear at echocardiography, which remains the most often used imaging tool.
METHODS
We studied 1,187 consecutive patients evaluated at 3 referral centers for CA and analyzed morphological, functional, and strain-derived echocardiogram parameters with the aim of developing a score-based diagnostic algorithm. Cardiac amyloid burden was quantified by using extracellular volume measurements at cardiac magnetic resonance.
RESULTS
A total of 332 patients were diagnosed with AL amyloidosis and 339 patients with transthyretin CA. Concentric remodeling and strain-derived parameters displayed the best diagnostic performance. A multivariable logistic regression model incorporating relative wall thickness, E wave/e' wave ratio, longitudinal strain, and tricuspid annular plane systolic excursion had the greatest diagnostic performance in AL amyloidosis (area under the curve: 0.90; 95% confidence interval: 0.87 to 0.92), whereas the addition of septal apical-to-base ratio yielded the best diagnostic accuracy in the increased heart wall thickness group (area under the curve: 0.80; 95% confidence interval: 0.85 to 0.90).
CONCLUSIONS
Specific functional and structural parameters characterize different burdens of CA deposition with different diagnostic performances and enable the definition of 2 scores that are sensitive and specific tools with which diagnose or exclude CA.
Topics: Aged; Aged, 80 and over; Amyloid Neuropathies, Familial; Biopsy; Cardiomyopathy, Hypertrophic; Diagnosis, Differential; Echocardiography; Europe; Female; Humans; Immunoglobulin Light-chain Amyloidosis; Magnetic Resonance Imaging; Male; Middle Aged; Myocardium; Predictive Value of Tests; Ventricular Function, Left; Ventricular Remodeling
PubMed: 31864973
DOI: 10.1016/j.jcmg.2019.10.011 -
Methodist DeBakey Cardiovascular Journal 2022Amyloidosis encompasses a collection of disorders of pathological protein folding. The extracellular location where these "amyloid fibril" proteins are deposited... (Review)
Review
Amyloidosis encompasses a collection of disorders of pathological protein folding. The extracellular location where these "amyloid fibril" proteins are deposited determines the clinical presentation of the disease. The abnormal architecture of these fibrils makes them insoluble and not easily removed, leading to disruption of normal tissue structure and interference with normal physiology. Amyloidosis of the heart and kidney can be inherited, secondary to unrelated diseases, or due to a plasma cell disorder. This review will focus on immunoglobulin light chain amyloidosis, which is life-threatening and must be diagnosed as early as possible by employing precise and accurate typing to ensure timely and frequently curative therapy.
Topics: Amyloid; Amyloidosis; Heart; Humans; Immunoglobulin Light-chain Amyloidosis; Kidney
PubMed: 36132587
DOI: 10.14797/mdcvj.1150 -
Journal of UOEH 2021A 75-year-old-man experienced liver dysfunction and was diagnosed with decompensated liver cirrhosis. His serum hepatocyte growth factor (HGF) was very high (16.24...
A 75-year-old-man experienced liver dysfunction and was diagnosed with decompensated liver cirrhosis. His serum hepatocyte growth factor (HGF) was very high (16.24 ng/ml). Because the etiology was unclear, we considered the possibility of amyloidosis. Biopsy of the mucosa of the stomach, duodenum and rectum demonstrated amyloid deposition. From the findings of Congo red staining and immunohistochemical analyses, we made a diagnosis of systemic amyloid light-chain amyloidosis. Unfortunately, the patient died one month after the diagnosis. We considered that serum HGF was useful for the diagnosis and prediction of prognosis of primary systemic amyloidosis.
Topics: Aged; Amyloidosis; Biopsy; Hepatocyte Growth Factor; Humans; Immunoglobulin Light-chain Amyloidosis; Stomach
PubMed: 34092767
DOI: 10.7888/juoeh.43.227 -
Hematology/oncology Clinics of North... Dec 2020Opportunities and challenges in the field of systemic amyloidosis can be grouped into 4 categories. First, a deeper understanding of the pathogenesis of the disease is... (Review)
Review
Opportunities and challenges in the field of systemic amyloidosis can be grouped into 4 categories. First, a deeper understanding of the pathogenesis of the disease is required. Second, a greater awareness of the disease, which will lead to an earlier diagnosis, is imperative. Third, end points for interventional trials are required to convey us to our fourth aspirations, which are novel therapies for patients with light chain amyloidosis.
Topics: Clinical Trials as Topic; Humans; Immunoglobulin Light-chain Amyloidosis
PubMed: 33099434
DOI: 10.1016/j.hoc.2020.08.009 -
International Journal of Molecular... Dec 2021Cardiac involvement has a profound effect on the prognosis of patients with systemic amyloidosis. Therapeutic methods for suppressing the production of causative... (Review)
Review
Cardiac involvement has a profound effect on the prognosis of patients with systemic amyloidosis. Therapeutic methods for suppressing the production of causative proteins have been developed for ATTR amyloidosis and AL amyloidosis, which show cardiac involvement, and the prognosis has been improved. However, a method for removing deposited amyloid has not been established. Methods for reducing cytotoxicity caused by amyloid deposition and amyloid precursor protein to protect cardiovascular cells are also needed. In this review, we outline the molecular mechanisms and treatments of cardiac amyloidosis.
Topics: Amyloid Neuropathies, Familial; Animals; Cardiomyopathies; Heart; Humans; Immunoglobulin Light-chain Amyloidosis; Prognosis
PubMed: 35008444
DOI: 10.3390/ijms23010025 -
Current Cardiology Reports Jul 2022This review will explore the role of cardiac imaging in guiding treatment in the two most commonly encountered subtypes of cardiac amyloidosis (immunoglobulin... (Review)
Review
PURPOSE OF REVIEW
This review will explore the role of cardiac imaging in guiding treatment in the two most commonly encountered subtypes of cardiac amyloidosis (immunoglobulin light-chain amyloidosis [AL] and transthyretin amyloidosis [ATTR]).
RECENT FINDINGS
Advances in multi-parametric cardiac imaging involving a combination of bone scintigraphy, echocardiography and cardiac magnetic resonance imaging have resulted in earlier diagnosis and initiation of treatment, while the evolution of techniques such as longitudinal strain and extracellular volume quantification allow clinicians to track individuals' response to treatment. Imaging developments have led to a deeper understanding of the disease process and treatment mechanisms, which in combination result in improved patient outcomes. The rapidly expanding treatment regimens for cardiac amyloidosis have led to an even greater reliance on cardiac imaging to help establish an accurate diagnosis, monitor treatment response and aid the adjustment of treatment strategies accordingly.
Topics: Amyloid Neuropathies, Familial; Cardiac Imaging Techniques; Cardiomyopathies; Echocardiography; Humans; Immunoglobulin Light-chain Amyloidosis
PubMed: 35524881
DOI: 10.1007/s11886-022-01703-7 -
Blood Oct 2023Amyloid light-chain (AL) amyloidosis is a rare, typically fatal disease characterized by the accumulation of misfolded immunoglobulin light chains (LCs). Birtamimab is... (Randomized Controlled Trial)
Randomized Controlled Trial
Amyloid light-chain (AL) amyloidosis is a rare, typically fatal disease characterized by the accumulation of misfolded immunoglobulin light chains (LCs). Birtamimab is an investigational humanized monoclonal antibody designed to neutralize toxic LC aggregates and deplete insoluble organ-deposited amyloid via macrophage-induced phagocytosis. VITAL was a phase 3 randomized, double-blind, placebo-controlled clinical trial assessing the efficacy and safety of birtamimab + standard of care (SOC) in 260 newly diagnosed, treatment-naive patients with AL amyloidosis. Patients received 24 mg/kg IV birtamimab + SOC or placebo + SOC every 28 days. The primary composite end point was the time to all-cause mortality (ACM) or centrally adjudicated cardiac hospitalization ≥91 days after the first study drug infusion. The trial was terminated early after an interim futility analysis; there was no significant difference in the primary composite end point (hazard ratio [HR], 0.826; 95% confidence interval [CI], 0.574-1.189; log-rank P = .303). A post hoc analysis of patients with Mayo stage IV AL amyloidosis, those at the highest risk of early mortality, showed significant improvement in the time to ACM with birtamimab at month 9 (HR, 0.413; 95% CI, 0.191-0.895; log-rank P = .021). At month 9, 74% of patients with Mayo stage IV AL amyloidosis treated with birtamimab and 49% of those given placebo survived. Overall, the rates of treatment-emergent adverse events (TEAEs) and serious TEAEs were generally similar between treatment arms. A confirmatory phase 3 randomized, double-blind, placebo-controlled clinical trial of birtamimab in patients with Mayo stage IV AL amyloidosis (AFFIRM-AL; NCT04973137) is currently enrolling. The VITAL trial was registered at www.clinicaltrials.gov as #NCT02312206.
Topics: Humans; Immunoglobulin Light-chain Amyloidosis; Standard of Care; Antibodies, Monoclonal, Humanized; Amyloidosis; Double-Blind Method; Treatment Outcome
PubMed: 37366170
DOI: 10.1182/blood.2022019406 -
Methodist DeBakey Cardiovascular Journal 2022Amyloidosis is a disorder of protein misfolding and metabolism in which insoluble fibrils are deposited in various tissues, causing organ dysfunction and eventually... (Review)
Review
Amyloidosis is a disorder of protein misfolding and metabolism in which insoluble fibrils are deposited in various tissues, causing organ dysfunction and eventually death. Out of the 60-plus heterogeneous amyloidogenic proteins that have been identified, approximately 30 are associated with human disease. The unifying feature of these proteins is their tendency to form beta-pleated sheets aligned in an antiparallel fashion. These sheets then form rigid, nonbranching fibrils that resist proteolysis, causing mechanical disruption and local oxidative stress in affected organs such as the heart, liver, kidneys, nervous system, and gastrointestinal tract. Here we review the epidemiology of light chain amyloidosis, the staging, and the concomitant prognostication that is critical in determining the appropriate treatment.
Topics: Amyloidosis; Humans; Immunoglobulin Light-chain Amyloidosis
PubMed: 35414848
DOI: 10.14797/mdcvj.1070 -
Journal of the National Comprehensive... Jan 2023Immunoglobulin light chain (AL) amyloidosis is a clonal plasma cell disorder with multiple clinical presentations. The diagnosis of AL amyloidosis requires a high index... (Review)
Review
Immunoglobulin light chain (AL) amyloidosis is a clonal plasma cell disorder with multiple clinical presentations. The diagnosis of AL amyloidosis requires a high index of suspicion, making a delay in diagnosis common, which contributes to the high early mortality seen in this disease. Establishing the diagnosis of AL amyloidosis requires the demonstration of tissue deposition of amyloid fibrils. A bone marrow biopsy and fat pad aspirate performed concurrently have a high sensitivity for the diagnosis of AL amyloidosis and negate the need for organ biopsies in most patients. An accurate diagnosis requires amyloid typing via additional testing, including tissue mass spectrometry. Prognostication for AL amyloidosis is largely driven by the organs impacted. Cardiac involvement represents the single most important prognostic marker, and the existing staging systems are driven by cardiac biomarkers. Apart from organ involvement, plasma cell percentage on the bone marrow biopsy, specific fluorescence in situ hybridization findings, age at diagnosis, and performance status are important prognostic markers. This review elaborates on the diagnostic testing and prognostication for patients with newly diagnosed AL amyloidosis.
Topics: Humans; Immunoglobulin Light-chain Amyloidosis; Amyloidosis; In Situ Hybridization, Fluorescence; Plasma Cells; Risk Assessment
PubMed: 36630897
DOI: 10.6004/jnccn.2022.7077 -
JACC. Cardiovascular Imaging Nov 2019Cardiac involvement drives prognosis and treatment choices in cardiac amyloidosis. Echocardiography is the first-line examination for patients presenting with heart... (Review)
Review
Cardiac involvement drives prognosis and treatment choices in cardiac amyloidosis. Echocardiography is the first-line examination for patients presenting with heart failure, and it is the imaging modality that most often raises the suspicion of cardiac amyloidosis. Echocardiography can provide an assessment of the likelihood of cardiac amyloid infiltration versus other hypertrophic phenocopies and can assess the severity of cardiac involvement. Visualizing myocardial amyloid infiltration is challenging and, until recently, was restricted to the domain of the pathologist. Two tests are transforming this: cardiac magnetic resonance (CMR) imaging and bone scintigraphy. After the administration of contrast, CMR is highly sensitive and specific for the 2 main types of ventricular myocardial amyloidosis, light chain amyloidosis (AL) and transthyretin amyloidosis (ATTR). CMR structural and functional assessment combined with tissue characterization can redefine cardiac involvement by tracking different disease processes, ranging from amyloid infiltration, to the myocardial response associated with amyloid deposition, through the visualization and quantification of myocardial edema and myocyte response. Bone scintigraphy (paired with exclusion of serum free light chains) is emerging as the technique of choice for distinguishing ATTR from light chain cardiac amyloidosis and other cardiomyopathies; it has transformed the diagnostic pathway for ATTR, allowing noninvasive diagnosis of ATTR without the need for a tissue biopsy in the majority of patients. CMR with tissue characterization and bone scintigraphy are rewriting disease understanding, classification, and definition, and leading to a change in patient care.
Topics: Amyloid Neuropathies, Familial; Cardiomyopathies; Diagnosis, Differential; Extracellular Space; Fibrosis; Humans; Immunoglobulin Light-chain Amyloidosis; Magnetic Resonance Imaging; Myocardium; Predictive Value of Tests; Radionuclide Imaging; Reproducibility of Results; Ventricular Remodeling
PubMed: 31422120
DOI: 10.1016/j.jcmg.2019.06.023