scholarly journals 325 Dealing with cardiac amyloidosis diagnosis: keep calm and use the magnifying glasses!

2021 ◽  
Vol 23 (Supplement_G) ◽  
Author(s):  
Laura De Michieli ◽  
Luca Licchelli ◽  
Giulio Sinigiani ◽  
Tamara Berno ◽  
Mila Della Barbera ◽  
...  
Keyword(s):  
Heart Failure ◽  
Bone Marrow ◽  
Cardiac Amyloidosis ◽  
Amyloid Fibril ◽  
Light Chains ◽  
Al Amyloidosis ◽  
Fat Pad ◽  
Cardiac Amyloid ◽  
Amyloid Fibril Protein

Abstract Methods and results Case report— male, 71 years old. Past medical history—arterial hypertension, dyslipidemia, tobacco abuse. COPD on nocturnal CPAP therapy. Rheumatic polymyalgia on steroid therapy. Previous unprovoked deep vein thrombosis on anticoagulation with rivaroxaban. Bilateral carpal tunnel surgeries 8 years ago. Spontaneous left biceps tendon rupture 4 year ago. IgA kappa monoclonal gammopathy of undetermined significance (MGUS). Mild interventricular septum (IVS) hypertrophy on echocardiography since 2018. In 2019 IVS was 18 mm with granular sparkling appearance. In February 2020 he was hospitalized for initial heart failure and COPD exacerbation. In 2021 he developed worsening dyspnoea. He underwent cardiological evaluation in a spoke hospital and a cardiac magnetic resonance (CMR) suggested infiltrative cardiomyopathy. Bone scintigraphy showed moderate cardiac uptake (Perugini Score 2). Following haematological evaluation, fat pad biopsy was performed, and amyloid was detected on Congo red staining. Classification of the amyloid fibril protein was not performed. Bone marrow biopsy, even though of suboptimal quality, was negative for amyloid and for plasma cellular infiltration. Bone marrow aspirate showed 11% of plasma cells and multiple myeloma was therefore hypothesized. Recent medical history—he was evaluated in our Cardiac Amyloid Outpatient Clinic in May 2021. He was symptomatic for dyspnoea (NYHA class III) and exercise intolerance, diffuse osteo-muscolar pain, and extremities paresthesia. His blood pressure was on the low side of normality with necessity of anti-hypertensive therapy downgrading. Signs and symptoms of hematological disease were not present. We required to analyse the fat pad specimen in order to perform amyloid fibril protein typing; with immunoelectron microscopy, transthyretin (TTR) was identified as the amyloid fibrils precursor (no light chains could be identified). We considered performing endomyocardial biopsy to exclude the coexistence of ATTR amyloidosis and light chains (AL) amyloidosis in the heart but, given the history, clinical picture, and fat pad biopsy results, we felt that cardiac ATTR was the most probable diagnosis and we decided to proceed with a close cardiological and haematological follow-up. TTR genetic testing is ongoing. Conclusions  ATTR cardiac amyloidosis is an emerging cause of heart failure, especially with preserved ejection fraction, in the older population. However, these patients frequently present with dysproteinemias and bone marrow abnormalities, up to multiple myeloma, raising the issue of differential diagnosis between ATTR and AL amyloidosis. According to the latest European Consensus Document, in the presence of cardiac uptake at bone scintigraphy (Grades 1–3) and positive haematologic tests, histological confirmation (usually cardiac) is necessary to subtype amyloid infiltration. In our case, the patient had positive Congo Red-stained fat pad biopsy, but the typing of the amyloid deposition was not performed. After referral to a Center with a Cardiac Amyloid Outpatient Clinic with a specialized Pathology Unit, we could further proceed with diagnostic workup and identify the amyloid deposition as ATTR; of note, fat pad biopsy is positive in just 15–25% of ATTR amyloidosis. Moreover, close collaboration with Hematology was necessary to assess the risk of AL amyloidosis and to provide a close and targeted follow-up. Endomyocardial biopsy was not performed after consideration of the various elements suggestive for ATTR cardiac amyloidosis, but the patient will be evaluated periodically and closely to potentially reassess this decision.

scholarly journals Characterization of an amyloid fibril protein from senile cardiac amyloid.

1977 ◽  
Vol 146 (2) ◽  
pp. 631-636 ◽  
Author(s):  
P Westermark ◽  
J B Natvig ◽  
B Johansson
Keyword(s):  
Cardiac Amyloidosis ◽  
Amyloid Fibrils ◽  
Amyloid Fibril ◽  
Heart Tissue ◽  
Normal Heart ◽  
Cardiac Amyloid ◽  
Subunit Protein ◽  
Amyloid Fibril Protein

A protein, ASCA, is isolated from amyloid fibrils extracted from heart tissue of five different patients with senile cardiac amyloidosis (SCA). The proteins of all five patients showed immunological identity when reacted with an antiserum raised against one of the proteins. In contrast, no reaction was obtained with antisera against a variety of other amyloid proteins. The antiserum against the subunit protein of senile cardiac amyloid did not react with any other amyloid preparations tested, nor with extracts of normal heart tissue. Thus, the subunit protein appeared to be unique to senile heart amyloid. The protein could form fibrils in vitro, had a mol wt of about 6,000 daltons and the amino acid compositions investigated in two cases showed extensive similarities but were clearly different from that of protein AA of secondary amyloid fibrils.

Abnormal NT-ProBNP in AL Amyloidosis Patients without Cardiac Involvement at Diagnosis - A Predictor of Subsequent Cardiac Involvement.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1500-1500
Author(s):  
Ashutosh D. Wechalekar ◽  
Helen J. Lachmann ◽  
Julian D. Gillmore ◽  
Philip N. Hawkins
Keyword(s):  
Cardiac Amyloidosis ◽  
Cardiac Involvement ◽  
Myocardial Dysfunction ◽  
Posterior Wall ◽  
Left Ventricular ◽  
Al Amyloidosis ◽  
International Consensus ◽  
Cardiac Amyloid ◽  
Significant Difference

Abstract Cardiac involvement in AL amyloidosis is associated with a poor prognosis and greatly increased treatment related morbidity and mortality, and regression of cardiac amyloid deposits is extraordinarily slow following chemotherapy that suppresses the underlying aberrant light chain production. Diagnosis of cardiac amyloidosis is normally made by echocardiography, by which time significant diastolic dysfunction has usually developed. Atrial natriuretic peptides (ANP, BNP and its N-terminal fragment NT-ProBNP) are useful in early diagnosis of myocardial dysfunction. Serum NT-ProBNP concentration has been reported to be a promising marker of cardiac dysfunction in AL amyloidosis, and patients with normal NT-ProBNP values at diagnosis have superior outcomes. We report here the outcome of patients attending the UK National Amyloidosis Centre (NAC) who had elevated NT-ProBNP at diagnosis of AL amyloidosis but who did not have accompanying evidence of cardiac involvement using conventional consensus criteria. To exclude the confounding effect of renal failure which is associated with substantial elevation of NT-ProBNP, we studied patients with serum creatinine <150 μmol/L and creatinine clearance of >50ml/min at diagnosis in whom there was less than 10% change in renal function after treatment. AL type amyloidosis was confirmed in all patients histologically with corroborating genetic studies to robustly exclude hereditary amyloidosis as indicated. Organ involvement and responses/progression were defined according to recent international consensus criteria (Gertz et al 2005). 102 patients who had no evidence of cardiac involvement by these conventional parameters and who otherwise conformed with our study criteria were identified. Median creatinine was 87 μmol/L (44–128), albumin 33g/L (10–65), bilirubin 7 μmol/L (1–65) and alkaline phosphatase 89 units/L (36–2649). The median interventricular septal and left ventricular posterior wall thickness was 9 mm (7–11 mm). 62 (61%) patients had NT-ProBNP ≤ 35pMol/L at diagnosis while 40 (39%) had NT-ProBNP of >35 pMol/L. There was no significant difference in the baseline characteristics of either group. 5 patients in each group did not respond to the initial chemotherapy (p=0.46). With median follow-up of 60 months, 19/40 (47%) of patients with NT-ProBNP >35pMol/L at diagnosis developed evidence of cardiac involvement compared to only 6/62 (10%) of whose baseline NT-ProBNP was ≤ 35 pMol/L (p<0.001). The Kaplan-Meier estimated median overall survival has not been reached for either group but the estimated 7 year survival was significantly better in the group with NT-ProBNP of ≤35pMol/L compared to those with greater values (92% vs. 82%, p=0.03). In conclusion, these preliminary findings suggest that patients who have elevated NT-ProBNP concentration but no conventional evidence of cardiac involvement at diagnosis of AL amyloid appear to be at greater risk of developing cardiac amyloidosis during follow-up, and have a poorer prognosis. It reasonable to speculate that such patients have early cardiac involvement at diagnosis that cannot be identified by conventional non-invasive methods, and that their risk of subsequently developing clinically significant cardiac amyloidosis may be reduced by striving to achieve complete remission of their underling clonal plasma cell disease.

scholarly journals Long-term Follow-up of Plasma Cells in Bone Marrow and Serum Free Light Chains in Primary Systemic AL Amyloidosis

2008 ◽  
Vol 47 (20) ◽  
pp. 1783-1790 ◽  
Author(s):  
Takuhiro Yoshida ◽  
Masayuki Matsuda ◽  
Nagaaki Katoh ◽  
Ko-ichi Tazawa ◽  
Yasuhiro Shimojima ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Plasma Cells ◽  
Light Chains ◽  
Al Amyloidosis ◽  
Free Light Chains ◽  
Serum Free ◽  
Long Term Follow Up ◽  
Serum Free Light Chains

Regression of cardiac amyloid deposits with novel therapeutics: reaching new frontiers in cardiac ATTR amyloidosis

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
L Chacko ◽  
A Martinez-Naharro ◽  
T Kotecha ◽  
R Martone ◽  
D Hutt ◽  
...  
Keyword(s):  
Treatment Group ◽  
Cardiac Amyloidosis ◽  
T1 Mapping ◽  
Group Versus ◽  
Control Group ◽  
Cardiac Amyloid ◽  
Attr Amyloidosis ◽  
Amyloid Load ◽  
The Impact

Abstract Background Cardiac involvement is the main driver of outcome in ATTR amyloidosis. Advances in therapeutics hold potential in transforming the course of the disease but the impact on cardiac amyloid load is unknown. The aim of this study was to evaluate the impact of patisiran, a new double stranded RNA based gene silencing therapy and a stabilizer, diflunisal, on cardiac amyloid load as measured by CMR and T1 mapping, in patients with ATTR amyloidosis. Methods and results Thirty-two patients with hereditary cardiac amyloidosis were studied. Sixteen patients received treatment with patisiran, and sixteen control subjects did not receive any disease modifying treatment. Patients were assessed with echocardiogram, CMR, NT-proBNP and six-minute walk time measurements at baseline and at 1 year (Mean interval 11.45±3.08 months in treatment group, mean interval 12.82±5.06 months in the control group). CMR analysis comprised LV volumes, T1 mapping to measure the extracellular volume (ECV) occupied by amyloid, T2 mapping and late gadolinium enhancement imaging. At 1-year follow-up, there was a substantial reduction in cardiac amyloid burden, in keeping with cardiac amyloid regression in 45% of patients on treatment. Overall the treatment group showed a reduction in ECV at 1 year follow up compared to an increase in ECV at 1 year in the control group (−1.37%, 95% CI: −3.43 to 0.68% versus 5.02%, 95% CI: 2.86% to 7.18% respectively, p<0.001). The treatment group also showed an improvement in change in 6MWT at 1 year follow up compared to 6MWT at 1 year in the control group (−8.12 meters, 95% CI: −50.8 to 34.6 meters in the treatment group versus −132.27 meters, 95% CI: −216 to −48.6 meters in the control group, p=0.002). The treatment group showed a reduction in BNP at 1 year follow up compared to an increase in the control group (−567.87, 95% CI: −1288.90 to 153.15 in the treatment group versus 2004, 95% CI: 12.82 to 3995.45 in the control group, p<0.001). There was no significant difference from baseline and 1-year data between the control and treatment groups for the difference in echocardiographic parameters, native T1, T2. There was a significant reduction in the percentage of injected dose by 99Tc-DPD scintigraphy in treated patients at 1 year compared to baseline. Conclusions These findings provide the first compelling evidence of substantial cardiac amyloid regression in ATTR amyloidosis, as well as the potential for CMR to be used to track response in treated patients with ATTR cardiac amyloidosis. Combination therapy with transthyretin knock down and stabilizing agents may well be synergistic given enhanced stoichiometry of stabilizers in the face of much reduced plasma transthyretin concentration. Funding Acknowledgement Type of funding source: None

scholarly journals Multimodality imaging can shift the clinical approach and prognosis of a patient: from heart failure and angina to cardiac amyloidosis

2021 ◽  
Vol 31 (1) ◽  
pp. 103-110
Author(s):  
Alexandra Maria Chitroceanu ◽  
Alina Ioana Nicula ◽  
Roxana Cristina Rimbas ◽  
Mihaela Andreescu ◽  
Cristina Popp ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Amyloidosis ◽  
Multimodality Imaging ◽  
Clinical Status ◽  
Decompensated Heart Failure ◽  
Response To Therapy ◽  
Al Amyloidosis ◽  
Clinical Approach ◽  
Non Invasive ◽  
Life Threatening

AL (light chain) amyloidosis is a life threatening disease. Untreated patients with involvement of the heart, a condition known as cardiac amyloidosis (CA), tend to have the most rapid disease progression and worst prognosis. Therefore, it is essential to early recognize the signs of symptoms of CA, and to identify the affected individuals with readily available non-invasive tests, as timely therapy can prolong life. Different imaging tests are used to diagnose and stratify the risk of the disease noninvasively, and to follow-up of the disease course and response to therapy. In this light, we present a case of a woman with cardiovascular risk factors, initially admitted for typical angina and decompensated heart failure (HF), who was later diagnosed with AL amyloidosis with cardiac involvement, by using multimodality imaging assessment in a step-by-step fashion. This changed completely the prognosis of the patient. Timely chemotherapy and stem cell transplantation led to an improvement in clinical status, biomarkers, and in a regression of amyloid myocardial infi ltration showed by imaging.

scholarly journals Diagnosis of Cardiac Amyloidosis Using Non-Invasive Technics

2021 ◽  
Author(s):  
Eva Strickler ◽  
Ernest Tsiaze ◽  
Gerrit Hellige ◽  
Dominik Zumstein ◽  
Dominik Waldmeier ◽  
...  
Keyword(s):  
Cardiac Amyloidosis ◽  
Al Amyloidosis ◽  
Definite Diagnosis ◽  
Diagnostic Features ◽  
Transthyretin Amyloidosis ◽  
Cardiac Amyloid ◽  
Non Invasive ◽  
Amyloid Accumulation ◽  
Clinically Significant ◽  
Multiorgan Disease

Amyloidosis is a rare multiorgan disease defined by a process of irreversible, extracellular accumulation of fibrillar proteins in the tissues, including the heart. Cardiac involvement is seen in most forms of amyloidosis, but it is frequently present and clinically significant in light chain (AL)-amyloidosis as well as transthyretin amyloidosis (ATTR). Cardiac amyloid accumulation leads to a restrictive filling pattern, which must be differentiated from other forms of restrictive and hypertrophic cardiomyopathies due to consequences for the treatment. Evolving knowledge of the disease has led to a definite diagnosis of the cardiac amyloidosis (CA) using non-invasive and low-risk diagnostic features, such as scintigraphy (gamma scan) and cardiovascular magnetic resonance (CMR) imaging using late gadolinium enhancement (LGE) and T1 mapping technics. The availability and diagnostic accuracy of these technics has reduced the need for cardiac biopsy. In the following chapter, we will describe common types of CA, the basic concepts, and updates of non-invasive diagnostic features.

Expression of Human Amyloidogenic Immunoglobulin Light Chains in Mice Leads to Organ Toxicity.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3412-3412
Author(s):  
Jennifer E. Ward ◽  
Daniel Brenner ◽  
Lei Cui ◽  
Ronglih Liao ◽  
Lawreen H. Connors ◽  
...  
Keyword(s):  
Amyloid Fibril ◽  
Light Chains ◽  
Al Amyloidosis ◽  
Immunoglobulin Light Chains ◽  
Short Term ◽  
Cmv Promoter ◽  
Heart Rates ◽  
Amyloidogenic Proteins ◽  
Protein Deposits

Abstract Recent evidence from the study of different amyloidogenic proteins challenges the dogma that tissue damage is solely the result of amyloid fibril deposition. To examine whether amyloidogenic human immunoglobulin light chains (LCs) may cause acute toxic effects prior to the development of fibrillar tissue deposits in vivo, we have generated amyloidogenic LC-expressing cell lines and transplanted them into mice. A full length lambda-6 light chain was cloned from cDNA prepared from bone marrow of a patient with aggressive multi-organ AL amyloidosis. The LC was subcloned into an expression vector with a CMV promoter and transfected into SP2/0 plasmacytoma cells. Stably transfected cells were injected into syngeneic Balb/c and RAG−/− mice. Four-six weeks later, echocardiograms were performed and the mice were euthanized and serum, urine, and tissues were collected. Mice injected with LC-producing cells, but not control untransfected SP2/0 cells, had detectable circulating human LC in their serum, and 6 of 9 RAG−/− mice excreted LC and albumin in the urine. These mice had evidence of bradycardia by echocardiography, with 4 of 12 mice having heart rates lower than 500 bpm while no controls had heart rates that low, and upregulation of markers of cell stress in the heart. In the kidney, there was evidence of amorphous protein deposits and early glomerulopathy by electron microscopy in two mice examined, but no fibril deposition. Thus, short-term expression of human amyloidogenic LC in mice in vivo produces alterations in heart and kidney function prior to the development of fibrillar deposits.

High Dose Melphalan with Autologous Stem Cell Transplantation Overcomes Poor Prognosis of Primary Amyloidosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1350-1350
Author(s):  
Simrit Parmar ◽  
Mubeen Khan ◽  
Gabriela Rondon ◽  
Nina Shah ◽  
Qaiser Bashir ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Plasma Cells ◽  
High Dose ◽  
Al Amyloidosis ◽  
Hematologic Response ◽  
Bone Marrow Plasma ◽  
Organ Response ◽  
High Dose Melphalan

Abstract Abstract 1350 Background: Systemic Primary AL Amyloidosis is a rare but potentially fatal disease resulting from tissue deposits of amyloid fibrils derived from monoclonal immunoglobulin light chains. High-dose melphalan followed by autologous hematopoietic stem cell transplant (auto HCT) is associated with hematologic and organ responses and improved survival. Methods: In this retrospective analysis we identified 46 patients with primary AL amyloidosis who received auto HCT between 01/1998 to 05/2010 at MDACC. Organ responses were determined using Amyloidosis Consensus Criteria. Results: The median age at auto HSCT was 56 years (34-74) where 61% were males and 35% were older than 60 years of age. 61% had lambda light chain restriction and only 4% had cytogenetic abnormalities. Disease characteristics are summarized in Table 1. The median time from diagnosis to auto HCT was 6.6 months (2.2-29.4 months). 22 pts (47.8%) had one organ, 19 pts (41.3%) had 2 organ and 4 pts (8.7%) had 3 organ involvement. 11 pts (23.9%) had heart and 35 pts (76.1%) had kidney involvement. The median follow up from the time of diagnosis was 22.4 months and from time of auto HCT was 16.7 months. High dose Melphalan dose was 200mg/m2 in 24 pts (52%) and 140mg/m2 in 22 (47.8%). There were 4 early deaths and 4 pts whose follow up was less than 3 months and their response was not assessed. Out of the 38 evaluable patients, the post-transplant organ responses were as follows ≥PR 25(66%), ≥stable disease 35(92%) (Table2). The hematologic responses were: CR=5 (13%), ≥VGPR=10(26%), ≥PR=26 (68%), ≥SD=37(97%). One patient had progressive disease. There was a correlation between organ response and hematologic response (chi square;p<10-3). The day-100 treatment related mortality (TRM) was 8.7% and 1-yr TRM was 13%. The median progression-free (PFS) and overall survival (OS) from auto HCT was 73.8 months and not reached (from transplant). The median PFS and OS from diagnosis were 93 months and 59.8 months respectively. In multivariate analysis, heart involvement (p=0.01), female sex (p=0.011), age ≥60 years (p=0.002), bone marrow plasma cells≥10% (p=0.043) and Beta-2 microglobulin>3.5mg/l (p=0.02) were associated with poor OS. Improved OS correlated with organ response (52.6 vs 11.4 months; p=0.01) and hematologic response (52.6 vs.6.1months; p=0.002). Hemoglobin <10 g/dl (p=0.047), bone marrow plasma cells≥10% (p=0.043) and age≥60 years (p=0.075) were associated with shorter PFS. Hematologc response (p=0.48) and organ response (p=0.12) were not associated with improved PFS. Conclusion: In this analysis the outcome of patients with primary systemic AL amyloidosis was durable with auto HCT with acceptable mortality risk and improved survival. Disclosures: No relevant conflicts of interest to declare.

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