Light-Chain Cardiac Amyloidosis: A Heart With 2 Very Different Ventricles?
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SUBMITTER: Barge-Caballero G
PROVIDER: S-EPMC8288708 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Light chain (AL) amyloidosis is caused by a usually small plasma-cell clone that is able to produce the amyloidogenic light chains. They are able to misfold and aggregate, deposit in tissues in the form of amyloid fibrils and lead to irreversible organ dysfunction and eventually death if treatment is late or ineffective. Cardiac damage is the most important prognostic determinant. The risk of dialysis is predicted by the severity of renal involvement, defined by the baseline proteinuria and glomerular filtration rate, and by the response to therapy. The specific treatment is chemotherapy targeting the underlying plasma-cell clone. It needs to be risk-adapted, according to the severity of cardiac and/or multi-organ involvement. Autologous stem cell transplant (preceded by induction and/or followed by consolidation with bortezomib-based regimens) can be considered for low-risk patients (~20%). Bortezomib combined with alkylators is used in the majority of intermediate-risk patients, and with possible dose escalation in high-risk subjects. Novel, powerful anti-plasma cell agents were investigated in the relapsed/refractory setting, and are being moved to upfront therapy in clinical trials. In addition, the use of novel approaches based on antibodies targeting the amyloid deposits or small molecules interfering with the amyloidogenic process gave promising results in preliminary studies. Some of them are under evaluation in controlled trials. These molecules will probably add powerful complements to standard chemotherapy. The understanding of the specific molecular mechanisms of cardiac damage and the characteristics of the amyloidogenic clone are unveiling novel potential treatment approaches, moving towards a cure for this dreadful disease.
| S-EPMC5841939 | biostudies-literature
Project description:Amyloid light chain (AL) amyloidosis is a systemic disease characterised by the aggregation of misfolded immunoglobulin light chain (LC), predominantly in the heart and kidneys, causing organ failure. If untreated, the median survival of patients with cardiac AL amyloidosis is 6 months from the onset of heart failure. Protracted time to establish a diagnosis, often lasting >1 year, is a frequent factor in poor treatment outcomes. Cardiologists, to whom patients are often referred, frequently miss the opportunity to diagnose cardiac AL amyloidosis. Nearly all typical cardiac support measures, with the exception of diuretics, are ineffective and may even worsen clinical symptoms, emphasising the need for accurate diagnosis. Patients with severe cardiac involvement face poor outcomes; heart transplantation is rarely an option because of multiorgan involvement, rapid clinical decline and challenges in predicting which patients will respond to treatment of the underlying plasma cell disorder. Early diagnosis and prompt treatment with ââ'¬Ëœsource therapiesââ'¬â"¢ that limit the production of amyloidogenic LC are associated with better survival and improvement in organ function after a median of 2.4 months following haematological complete response. However, organ recovery is often incomplete because these source therapies do not directly target deposited amyloid. Emerging amyloid-directed therapies may attenuate, and potentially reverse, organ dysfunction by clearing existing amyloid and inhibiting fibril formation of circulating aggregates. Improved recognition of AL amyloidosis by cardiologists allows for earlier treatment and improved outcomes.
| S-EPMC5566095 | biostudies-literature
Project description:BackgroundWhile patients with cardiac transthyretin amyloidosis are easily diagnosed with bone scintigraphy, the detection of cardiac light chain (AL) amyloidosis is challenging. Cardiac magnetic resonance (CMR) analyses play an essential role in the differential diagnosis of cardiomyopathies; however, limited data are available from cardiac AL-Amyloidosis. Hence, the purpose of the present study was to analyze the potential role of CMR in the detection of cardiac AL-amyloidosis.MethodsWe included 35 patients with proved cardiac AL-amyloidosis and two control groups constituted by 330 patients with hypertrophic cardiomyopathy (HCM) and 70 patients with arterial hypertension (HT), who underwent CMR examination. The phenotype and degree of left ventricular (LV) hypertrophy and the amount and pattern of late gadolinium enhancement (LGE) were evaluated. In addition, global and regional LV strain parameters were also analyzed using feature-tracking techniques. Sensitivity and specificity of several CMR parameters were analyzed in diagnosing cardiac AL-amyloidosis.ResultsThe sensitivity and specificity of diffuse septal subendocardial LGE in diagnosing cardiac AL-amyloidosis was 88% and 100%, respectively. Likewise, the sensitivity and specificity of septal myocardial nulling prior to blood pool was 71% and 100%, respectively. In addition, a LV end-diastolic septal wall thickness ≥ 15 mm had an optimal diagnostic performance to differentiate cardiac AL-amyloidosis from HT (sensitivity 91%, specificity 89%). On the other hand, a reduced global LV longitudinal strain (< 15%) plus apical sparing (apex-to-base longitudinal strain > 2) had a very low sensitivity (6%) in detecting AL-Amyloidosis, but with very high specificity (100%).ConclusionsThe findings from this study suggest that CMR could have an optimal diagnostic performance in the diagnosis of cardiac AL-amyloidosis. Hence, further larger studies are warranted to validate the findings from this study.
| S-EPMC9191721 | biostudies-literature
Project description:BackgroundCardiac involvement in amyloid light-chain (AL) amyloidosis usually represents a brick in the wall of a multi-system disease. The presence of cardiac deposition of free light chains (FLCs) is the main determinant of survival. Isolated cardiac AL is an uncommon scenario characterized by a challenging diagnostic and therapeutic workup.Case summaryA 57-year-old asymptomatic man was presented for an incidental finding of myocardial necrosis at the electrocardiogram (ECG) performed for newly diagnosed arterial hypertension. Alongside signs of previous myocardial infarction, transthoracic echocardiography showed a severely increased left ventricular (LV) wall thickness not consistent with ECG voltages, segmental akinaesia with normal LV systolic function with 'apical sparing' pattern. Laboratory assessment showed an unexpectedly high level of natriuretic peptide and persistently abnormal troponin in the absence of symptoms or signs of heart failure or ongoing ischaemia. Coronary angiogram confirmed the coronary artery disease. Before revascularization, a complete diagnostic workup was carried. Serum electrophoresis detected a monoclonal gammopathy that was further investigated by serum immunofixation, revealing high lambda FLCs concentration. Fat pad, bone marrow, and salivary glands biopsies resulted negative for amyloid deposition. Finally, endomyocardial biopsy was consistent with AL amyloidosis. Urgent percutaneous revascularization was performed, and the patients was timely started on chemotherapy.DiscussionThe diagnosis of isolated cardiac AL amyloidosis is challenging and carries important therapeutic implications. As the short-term prognosis might be severely compromised, an accurate diagnostic flowchart has to be systematically pursued to obtain a precise diagnosis and address the optimal, tailored management.
| S-EPMC9998033 | biostudies-literature
Project description:BackgroundPatients with light chain (AL) amyloidosis who present with severe heart failure due to cardiac involvement rarely survive more than 6 months. Survival after cardiac transplantation is markedly reduced due to the progression of amyloidosis. Autologous stem-cell transplantation (ASCT) has become a common therapy for AL amyloidosis, but there is an exceedingly high treatment-related mortality in patients with heart failure.MethodsWe developed a treatment strategy of cardiac transplant followed by ASCT. Twenty-six patients were evaluated, and of 18 eligible patients, nine patients underwent cardiac transplantation. Eight of these patients subsequently received an ASCT.ResultsSix of seven evaluable patients achieved a complete hematologic remission, and one achieved a partial remission. At a median follow-up of 56 months from cardiac transplant, five of seven patients are alive without recurrent amyloidosis. Their survival is comparable with 17,389 patients who received heart transplants for nonamyloid heart disease: 64% in nonamyloid vs. 60% in amyloid patients at 7 years (P=0.83). Seven of eight transplanted patients have had no evidence of amyloid in their cardiac allograft.ConclusionsThis demonstrates that cardiac transplantation followed by ASCT is feasible in selected patients with AL amyloidosis and heart failure, and that such a strategy may lead to improved overall survival.
| S-EPMC2964067 | biostudies-literature
Project description:BackgroundLight-chain amyloidosis has always been described as a sporadic disease caused by plasma cell dyscrasia. Cardiac amyloidosis refers to cardiac involvement with infiltration of amyloid fibrils in the myocardium. The degree of cardiac involvement is the greatest predictor of prognosis. To our knowledge, AL cardiac amyloidosis has only been reported once before in first-degree relatives.Case summaryIn this report, we describe the unusual cases of two sisters with light-chain cardiac amyloidosis. The first patient underwent autologous stem cell transplantation and remained in remission for 10 years until the disease relapsed and she died of end-stage heart failure. The second patient was promptly started on a chemotherapy regimen but died shortly after her initial diagnosis due to rapid progression of cardiac dysfunction.ConclusionCardiac amyloidosis is a severe life-threatening condition which requires a multidisciplinary diagnostic and therapeutic approach. Based on this case report, a genetic cause for AL amyloidosis might be suspected or is this a purely coincidental finding? Counselling, screening, and follow-up of other family members are very challenging. As is often the case with rare diseases, many unsolved questions remain, representing important challenges for clinicians.
| S-EPMC8922710 | biostudies-literature
Project description:Light-chain amyloidosis (AL) is a fatal disorder wherein the immunoglobulin light chain misfolds and aggregates, leading to amyloid plaques in various organs. Patient-specific mutations in the light chain variable domain (VL) are tightly linked to amyloidosis, but how these mutations drive AL is unknown. In recent work, Rottenaicher et al. analyze five mutations found in the VL of a patient with cardiac AL. Their data suggest that decreased VL stability and increased flexibility in the core of the VL, caused by mutations outside of this core, could be key to aggregation and highlight the delicate balancing act required for antibody maturation to enable antigen recognition while not altering protein biophysics.
| S-EPMC8191319 | biostudies-literature
Project description:Light chain (AL) amyloidosis is the most common form of amyloidosis involving the kidney. It is characterized by albuminuria, progressing to overt nephrotic syndrome and eventually end-stage renal failure if diagnosed late or ineffectively treated, and in most cases by concomitant heart involvement. Cardiac amyloidosis is the main determinant of survival, whereas the risk of dialysis is predicted by baseline proteinuria and glomerular filtration rate, and by response to therapy. The backbone of treatment is chemotherapy targeting the underlying plasma cell clone, that needs to be risk-adapted due to the frailty of patients with AL amyloidosis who have cardiac and/or multiorgan involvement. Low-risk patients (?20%) can be considered for autologous stem cell transplantation that can be preceded by induction and/or followed by consolidation with bortezomib-based regimens. Bortezomib combined with alkylators, such as melphalan, preferred in patients harboring t(11;14), or cyclophosphamide, is used in most intermediate-risk patients, and with cautious dose escalation in high-risk subjects. Novel, powerful anti-plasma cell agents, such as pomalidomide, ixazomib, and daratumumab, prove effective in the relapsed/refractory setting, and are being moved to upfront therapy in clinical trials. Novel approaches based on small molecules interfering with the amyloidogenic process and on antibodies targeting the amyloid deposits gave promising results in preliminary uncontrolled studies, are being tested in controlled trials, and will likely prove powerful complements to chemotherapy. Finally, improvements in the understanding of the molecular mechanisms of organ damage are unveiling novel potential treatment targets, moving toward a cure for this dreadful disease.
| S-EPMC5976806 | biostudies-literature
Project description: Not available
| S-EPMC7364018 | biostudies-literature
Project description:ObjectivesThe purpose of this study was to determine phenotypes characterizing cardiac involvement in AL amyloidosis by using direct (fluorine-18-labeled florbetapir {[18F]florbetapir} positron emission tomography [PET]/computed tomography) and indirect (echocardiography and cardiac magnetic resonance [CMR]) imaging biomarkers of AL amyloidosis.BackgroundCardiac involvement in systemic light chain amyloidosis (AL) is the main determinant of prognosis and, therefore, guides management. The hypothesis of this study was that myocardial AL deposits and expansion of extracellular volume (ECV) could be identified before increases in N-terminal pro-B-type natriuretic peptide or wall thickness.MethodsA total of 45 subjects were prospectively enrolled in 3 groups: 25 with active AL amyloidosis with cardiac involvement (active-CA), 10 with active AL amyloidosis without cardiac involvement by conventional criteria (active-non-CA), and 10 with AL amyloidosis with cardiac involvement in remission for at least 1 year (remission-CA). All subjects underwent echocardiography, CMR, and [18F]florbetapir PET/CT to evaluate cardiac amyloid burden.ResultsThe active-CA group demonstrated the largest myocardial AL amyloid burden, quantified by [18F]florbetapir retention index (RI) 0.110 (interquartile range [IQR]: 0.078 to 0.139) min-1, and the lowest cardiac function by global longitudinal strain (GLS), median GLS -11% (IQR: -8% to -13%). The remission-CA group had expanded extracellular volume (ECV) and [18F]florbetapir RI of 0.097 (IQR: 0.070 to 0.124 min-1), and abnormal GLS despite hematologic remission for >1 year. The active-non-CA cohort had evidence of cardiac amyloid deposition by advanced imaging metrics in 50% of the subjects; cardiac involvement was identified by late gadolinium enhancement in 20%, elevated ECV in 20%, and elevated [18F]florbetapir RI in 50%.ConclusionsEvidence of cardiac amyloid infiltration was found based on direct and indirect imaging biomarkers in subjects without CA by conventional criteria. The findings from [18F]florbetapir PET imaging provided insight into the preclinical disease process and on the basis of interpretation of expanded ECV on CMR and have important implications for future research and clinical management of AL amyloidosis. (Molecular Imaging of Primary Amyloid Cardiomyopathy [MICA]; NCT02641145).
| S-EPMC8218539 | biostudies-literature