Effectiveness of Bortezomib in Cardiac AL Amyloidosis: A Report of Two Cases

Cardiac involvement is a major prognostic determinant in patients with primary AL amyloidosis. The clinical results of standard therapeutic approaches are suboptimal. It has been recently shown that bortezomib, an inhibitor of the proteasome, can induce rapid favourable responses in AL amyloidosis improving cardiac function and survival. Herein we report on two patients with cardiac amyloidosis treated by bortezomib who experienced partial or total remission of hematologic disease and of cardiac involvement. However, death of one patient, suffering from chronic kidney disease stage 5, due to fulminant respiratory syndrome suggests the need for caution in bortezomib use if patients have this comorbid condition.

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Diagnostic approach to light-chain cardiac amyloidosis and its differential diagnosis

Acta Haematologica Polonica ◽

10.2478/ahp-2018-0002 ◽

2018 ◽

Vol 49 (1) ◽

pp. 9-14

Author(s):

Monika Adamska ◽

Anna Komosa ◽

Tatiana Mularek ◽

Joanna Rupa-Matysek ◽

Lidia Gil

Keyword(s):

Differential Diagnosis ◽

Light Chain ◽

Cardiac Amyloidosis ◽

Cardiac Involvement ◽

Diagnosis And Treatment ◽

Diagnostic Approach ◽

Al Amyloidosis ◽

Delay In Diagnosis ◽

Light Chain Amyloidosis ◽

Novel Approaches

AbstractCardiac amyloidosis is a rare and often-misdiagnosed disorder. Among other forms of deposits affecting the heart, immunoglobulin-derived light-chain amyloidosis (AL amyloidosis) is the most serious form of the disease. Delay in diagnosis and treatment may have a major impact on the prognosis and outcomes of patients. This review focuses on the presentation of the disorder and current novel approaches to the diagnosis of cardiac involvement in AL amyloidosis.

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AL-amyloidosis with cardiac involvement. Diagnostic capabilities of non-invasive methods

Terapevticheskii arkhiv ◽

10.26442/00403660.2021.04.200689 ◽

2021 ◽

Vol 93 (4) ◽

pp. 487-496

Author(s):

Alexandra Ya. Gudkova ◽

Sergei V. Lapekin ◽

Tinatin G. Bezhanishvili ◽

Maria A. Trukshina ◽

Victoria G. Davydova ◽

...

Keyword(s):

Differential Diagnosis ◽

Cardiac Amyloidosis ◽

Cardiac Involvement ◽

Clinical Course ◽

Al Amyloidosis ◽

Transthyretin Amyloidosis ◽

Non Invasive ◽

Amyloid Cardiomyopathy ◽

Diagnostic Capabilities ◽

Invasive Diagnostics

There are presented the literature data and a description of the clinical course of the disease in isolated/predominant cardiac amyloidosis. Amyloid cardiomyopathy is the most common phenocopy of hypertrophic cardiomyopathy. The modern possibilities of non-invasive diagnostics using osteoscintigraphy for the differential diagnosis between amyloid cardiomyopathy caused by AL- and transthyretin amyloidosis are described in detail.

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Comparison of Different Techniques to Identify Cardiac Involvement in Immunoglobulin Light Chain Amyloidosis

Blood ◽

10.1182/blood-2018-99-117627 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3182-3182

Author(s):

Mohammed A Aljama ◽

M Hasib Sidiqi ◽

Angela Dispenzieri ◽

Morie A. Gertz ◽

Martha Q. Lacy ◽

...

Keyword(s):

Strain Rate ◽

Board Of Directors ◽

Light Chain ◽

Mayo Clinic ◽

Endomyocardial Biopsy ◽

Research Funding ◽

Cardiac Amyloidosis ◽

Cardiac Involvement ◽

Al Amyloidosis ◽

Advisory Committees

Abstract Background: Cardiac involvement is integral in staging and prognosis of immunoglobulin light chain (AL) amyloidosis. The N-terminal prohormone of brain natriuretic peptide (NT proBNP) is a cardiac biomarker used in screening for cardiac involvement and staging the disease. Transthoracic echocardiogram (TTE) and cardiac magnetic resonance (CMR) are the imaging modalities recommended to determine cardiac involvement and function. Methods: We conducted a retrospective review of all patients with biopsy proven systemic AL amyloidosis seen at the mayo clinic between Jan 1, 2006 and Dec 30, 2015. The aim of the study is to identify the nature of abnormalities in cardiac biomarkers and echocardiographic features in patients with AL amyloidosis and the ability of these investigations to diagnose cardiac involvement. We first identified all patients with AL amyloidosis that underwent endomyocardial biopsy for suspicion of cardiac involvement (Cohort 1). We then analyzed a cohort (Cohort 2) which consisted of patients who had serum NT proBNP and a comprehensive echocardiographic evaluation at time of diagnosis. Results: 179 patients with AL amyloidosis underwent endomyocardial biopsy (Cohort 1) of whom 173 had evidence of amyloid deposition. In this cohort, 159 patients had NT proBNP performed at the time of the procedure. The NT proBNP was elevated (>300) in all 159 patients with a median NT proBNP of 4917 (range 355-69541). The median left ventricular ejection fraction (LVEF), interventricular septal (IVS) thickness and strain rate were 54 (range 10-77), 15 (range 8-30) and -9 (range -21 to 0) respectively. CMR findings were consistent or suggestive of light chain amyloidosis in 38/42 patients, yielding a sensitivity of 90 percent. The LVEF, IVS thickness and strain rate were abnormal in 89/168 (53%), 102/64 (61%) and 92/95 (97%) respectively. 95 patients with biopsy proven cardiac amyloidosis had complete echocardiogram data available on LVEF, IVS thickness and strain rate, with 97% (n=92) presenting with an abnormality in at least one of these variables . CMR findings were consistent or suggestive of light chain amyloidosis in 38/42 patients, yielding a sensitivity of 90 percent. Patients with a normal NT proBNP and normal echocardiogram were considered disease free (true negative), based on our initial analysis of these investigations in Cohort 1. Cohort 2 consisted of 342 consecutive patients. The median NT pro BNP was 1878 (25-48214). The median LVEF, IVS thickness and strain rate were 63 (22-90), 14 (6-25) and -13 (-25 to -3) respectively. 259 (76%) patients had a positive NT proBNP (above 300), of whom 237 (92%) had an abnormality detected on TTE. 83 patients had a negative NT proBNP, of whom 27 (33%) had an abnormality in either LVEF, IVS thickness or strain rate. 19 of these 27 patients had a borderline reduced strain rate between -17 and -18, whilst the remaining 8 patients had a strain between -14 and -15. Only 6/27 patients were considered to have possible early cardiac involvement and none have any other diagnostic or classical features of amyloidosis on TTE. Conclusion: The combination of NT proBNP and comprehensive echocardiographic evaluation provides substantial information to diagnose cardiac amyloidosis in a significant portion of patients negating the need for endomyocardial biopsy. A negative NT proBNP rules out clinically meaningful cardiac involvement and may obviate the routine use of TTE in patients with a low clinical suspicion of cardiac amyloidosis. Disclosures Dispenzieri: Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Gertz:Research to Practice: Consultancy; Physicians Education Resource: Consultancy; Ionis: Honoraria; celgene: Consultancy; spectrum: Consultancy, Honoraria; Teva: Consultancy; Amgen: Consultancy; Medscape: Consultancy; janssen: Consultancy; Alnylam: Honoraria; Abbvie: Consultancy; annexon: Consultancy; Apellis: Consultancy; Prothena: Honoraria. Lacy:Celgene: Research Funding. Dingli:Millennium Takeda: Research Funding; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Kumar:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Roche: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Conventional physical examination extended by bedside ultrasound: a new paradigm in nephrological practice

Brazilian Journal of Nephrology ◽

10.1590/2175-8239-jbn-2020-0069 ◽

2020 ◽

Author(s):

Ana Cláudia da Silva ◽

Fabiana Oliveira Bastos Bonato ◽

Marcus Gomes Bastos

Keyword(s):

Nephrotic Syndrome ◽

Urinary Tract ◽

Physical Examination ◽

Cardiac Amyloidosis ◽

Cardiac Involvement ◽

Point Of Care ◽

Al Amyloidosis ◽

Point Of Care Ultrasound ◽

Pulmonary Congestion ◽

New Paradigm

ABSTRACT Point-of-Care Ultrasound (POCUS) has been gaining momentum as an extension to physical examination in several specialties. In nephrology, POCUS has generally been used in a restricted way in urinary tract evaluation. We report the case of a patient with nephrotic syndrome secondary to amyloidosis, previously diagnosed by renal biopsy, who was oligosymptomatic when seen the an outpatient clinic, where the POCUS, focused on the heart, lung and abdomen, revealed anasarca, pulmonary congestion and cardiac changes suggestive of cardiac amyloidosis. After evaluation by the cardiology and hematology services, the diagnosis of AL amyloidosis with cardiac involvement was confirmed. This case emphasizes the importance of extending the physical examination using POCUS, which, ideally, should not be restricted to the urinary tract.

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A Case Report of Cardiac Amyloidosis Highlighting the Importance of Strain Analysis

Case Reports in Cardiology ◽

10.1155/2021/5673364 ◽

2021 ◽

Vol 2021 ◽

pp. 1-5

Author(s):

Andres Cordova Sanchez ◽

Ryan Murphy ◽

Suman Rao ◽

Fidel Martinez ◽

Stephanie Bryant ◽

...

Keyword(s):

Heart Failure ◽

Case Report ◽

High Mortality ◽

Light Chain ◽

Cardiac Amyloidosis ◽

Inverse Relationship ◽

Cardiac Involvement ◽

Strain Analysis ◽

Al Amyloidosis ◽

Cardiac Symptoms

Cardiac involvement in light-chain (AL) amyloidosis has a high mortality. Once cardiac symptoms are present, it is important to make a diagnosis as there is an inverse relationship between mortality and time of diagnosis. Echocardiography is usually one of the first tests performed. But strain analysis, which can provide important clues, is not routinely performed. This is a case of AL amyloidosis presenting with heart failure in which echocardiographic strain analysis was vital for its diagnosis.

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Long Term Follow up of the Combination of Bortezomib with Dexamethasone as Initial Treatment for AL Amyloidosis

Blood ◽

10.1182/blood.v116.21.3048.3048 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3048-3048

Author(s):

Efstathios Kastritis ◽

Maria Roussou ◽

Magdalini Migkou ◽

Maria Gavriatopoulou ◽

Constantinos Pamboukas ◽

...

Keyword(s):

Initial Treatment ◽

Cardiac Amyloidosis ◽

Cardiac Involvement ◽

High Dose ◽

Al Amyloidosis ◽

Long Term Follow Up ◽

Organ Response ◽

High Dose Melphalan

Abstract Abstract 3048 Until recently, patients with AL amyloidosis had limited treatment options, especially those who were not candidates for high dose therapy, those with severe cardiac involvement or patients who relapsed after initial treatment or never responded to first line alkylators with steroids. Bortezomib (B) with dexamethasone (D) has shown significant activity in patients with AL amyloidosis in patients who relapsed or even those who were refractory to initial treatment. We and others have presented data indicating that BD is active in newly diagnosed patients with AL, inducing responses rapidly but also associated with high rates of complete responses. However, data about long-term follow-up of these patients are limited. Thus, we updated a series of 24, previously untreated patients who received frontline BD. In all patients, treatment started with B at a dose of 1.3 mg/m2 on days 1, 4, 8 & 11 and D was given for 4 consecutive days at a dose of 40 mg per day (days 1–4), every 21 days for up to 6 cycles. The median age of these patients was 70 years (range 42–82) and 46% were males. The median number of involved organs was 2; heart was involved in 83% and kidneys in 63%. Fifty-seven percent were Mayo stage II and 26% were Mayo stage III while 67% had impaired ECOG performance status ≥ 2. The first patient started treatment with BD on September 2005. A median of 5 cycles of BD was given (range 1–6) and 57% of patients received the planned 6 cycles. On intent to treat and according to criteria published by Gertz et al in 2005, 77% of patients achieved a hematologic response including 36% with a hematologic CR. Most of the responses occurred after the first cycle of BD (median time to first response <1 month), while a median of two cycles of BD was needed for CR (median time to CR was 42 days, range 21–84). In 54% of patients an organ response was recorded: 47% of patients with a cardiac involvement achieved a cardiac response and 77% had a reduction of NTproBNP ≥ 30% (which was at least 300 pg/ml), while 60% of patients with a kidney involvement achieved an organ response. Three patients received high dose melphalan with autologous stem cell transplant (HDM-ASCT) after they had completed 6 cycles of BD, 2 while in CR and one in PR. All these 3 patients had achieved organ responses before ASCT. The median follow up for all patients is 31 months. Thirteen patients (54%) have died; most of them due to complications of cardiac amyloidosis and the median survival is estimated to exceed 36 months (patients who underwent ASCT were censored at the time of HDM). Baseline NT-proBNP was the most significant factor independently associated with survival. There were no differences in the baseline characteristics of patients who achieved CR compared to those who achieved a PR as best hematologic response. The median follow up for patients who achieved a CR is 31 months (range 2–55 months). One patient died early due to complications of cardiac amyloidosis, while she had achieved a CR. Among the rest of the patients who achieved a CR but did not receive HDM, all remain alive and without progression for a median of 32 months. Similarly none of the patients who received HDM has relapsed. Among patients who achieved a PR as their best response, 4 (50%) have relapsed and the median progression free survival (PFS) for these patients is 9 months and their median survival is 34 months. In conclusion, BD induces high rates of CRs, in unselected, patients with previously untreated AL amyloidosis, most of whom had features of advanced disease and elevated cardiobiomarkers. i.e. patients that may be excluded form clinical trials. The severity of cardiac involvement remains the most important prognostic factor despite the rapid responses and the high rates of hematologic CRs. It is also of interest to note that CRs may persist even in patients who did not receive any alkylating agents or consolidation with high dose melphalan. A CR is associated with improved survival and should be the primary goal of treatment in patients with AL. Our data indicate that primary treatment with bortezomib based regimens should be evaluated in a phase III trial. Disclosures: Dimopoulos: Ortho-Biotech: Honoraria; Celgene: Honoraria; Millennium: Honoraria.

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Molecular Mechanisms of Cardiac Amyloidosis

International Journal of Molecular Sciences ◽

10.3390/ijms23010025 ◽

2021 ◽

Vol 23 (1) ◽

pp. 25

Author(s):

Yukihiro Saito ◽

Kazufumi Nakamura ◽

Hiroshi Ito

Keyword(s):

Amyloid Precursor Protein ◽

Cardiac Amyloidosis ◽

Molecular Mechanisms ◽

Cardiac Involvement ◽

Amyloid Deposition ◽

Precursor Protein ◽

Systemic Amyloidosis ◽

Al Amyloidosis ◽

Attr Amyloidosis ◽

Cardiovascular Cells

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.

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European Collaborative Study Defining Clinical Profile Outcomes and Novel Prognostic Criteria in Monoclonal Immunoglobulin M–Related Light Chain Amyloidosis

Journal of Clinical Oncology ◽

10.1200/jco.2015.63.3123 ◽

2016 ◽

Vol 34 (17) ◽

pp. 2037-2045 ◽

Cited By ~ 28

Author(s):

Sajitha Sachchithanantham ◽

Murielle Roussel ◽

Giovanni Palladini ◽

Catherine Klersy ◽

Shameem Mahmood ◽

...

Keyword(s):

Light Chain ◽

Cardiac Involvement ◽

Collaborative Study ◽

Immunoglobulin M ◽

Clinical Entity ◽

Disease Stage ◽

Response Criteria ◽

Liver Involvement ◽

Al Amyloidosis ◽

Hematologic Response

Purpose Immunoglobulin M (IgM)–related light chain (AL) amyloidosis, which accounts for 6% to 10% of all AL amyloidosis cases, is a rare and poorly studied clinical entity. Its natural history and management is not clearly defined. Prognostic and response criteria for AL amyloidosis in general have not been validated in this population. Patients and Methods We retrospectively gathered data for 250 patients diagnosed with IgM AL amyloidosis from three European amyloidosis centers. Clinical features, hematologic response, and overall survival (OS) were analyzed. The current staging and response criteria in non-IgM AL amyloidosis was applied to this series to assess its utility in this patient cohort. Results Patients with IgM AL amyloidosis have a significant IgM paraprotein (median, 10 g/L), less frequent lambda light chain isotype, and evaluable difference between involved and uninvolved free light chains (dFLCs; > 50 mg/L) in only two thirds of patients. Bone marrow showed clear non-Hodgkin lymphoma as the underlying disorder in 54% of patients. Cardiac involvement (45%) is less common but there is more frequent lymph node (20%) and neuropathic (28%) involvement compared with non-IgM AL. Fifty-seven percent of patients achieved a hematologic response (14% very good partial response/complete response [VGPR/CR]), with median OS not reached for patients achieving VGPR/CR, 64 months for PR, and 28 months for nonresponders (P < .001). On multivariate analysis, cardiac involvement, advanced Mayo disease stage, neuropathic involvement, and liver involvement were independent factors that had an impact on survival. Combining abnormal N-terminal pro-brain natriuretic peptide (NT-proBNP) and troponin T with liver involvement and the presence of neuropathy gives a better risk model: median OS of patients with none, one, or two or more abnormal factors was 90, 33, and 16 months, respectively. Conclusion IgM AL amyloidosis is a distinct clinical entity. Low-risk disease can be defined by combining cardiac involvement with novel prognostic markers. Deeper hematologic responses translate into improved outcomes, yet deep responses remain dismally poor, which highlights the urgent need for novel therapies.

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Free Light Chain Burden and Elevated Alkaline Phosphatase Identify Patients with Non-Cardiac AL Amyloidosis with Poor Outcome

Blood ◽

10.1182/blood.v124.21.3361.3361 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3361-3361

Author(s):

Giovanni Palladini ◽

Paolo Milani ◽

Andrea Foli ◽

Giampaolo Merlini

Keyword(s):

Alkaline Phosphatase ◽

Partial Response ◽

Cause Of Death ◽

Cardiac Amyloidosis ◽

Cardiac Involvement ◽

Stage I ◽

Liver Involvement ◽

Al Amyloidosis ◽

Heart Involvement

Abstract Background. The prognosis of patients with AL amyloidosis is mainly driven by the severity of heart involvement. Cardiac amyloidosis is being extensively studied, and accurate staging systems have been developed to identify patients with different degrees of heart dysfunction who are candidates for different treatment approaches. However, little is known on the outcome of patients without heart involvement who are generally considered low-risk. In the present study we evaluated factors affecting survival of patients with non-cardiac AL amyloidosis. Patients and Methods. The subjects (n=135) without cardiac involvement (NT-proBNP <332 ng/L and mean left ventricular wall thickness at echocardiography £12 mm) and with normal troponin (Mayo Clinic stage I) were selected form the prospectively maintained database including 748 consecutive, previously untreated patients with AL amyloidosis diagnosed at our center between 2004 and 2012. Results. Median age was 61 years (range 39-80 years). Involved organs were kidney (111, 82%); with median (range) proteinuria 7.2 g/24h (0.5-23.5 g/24h) and creatinine 1.1 mg/dL (0.5-4.4 mg/dL); soft tissues (21, 16%); liver (18, 13%), with median alkaline phosphatase (ALP) 2.3 times the upper reference limit (range 1.6-7.5 times u.r.l.); peripheral nervous system (13, 10%); gastrointestinal (GI) tract (10, 7%). One hundred seven patients (79%) had more than one organ involved. Median (range) bone marrow plasma cell infiltrate was 10% (2-29%) and dFLC (difference between involved and uninvolved free light chains) 70 mg/L (0-5721 mg/dL). Fifty-two patients (38%) were treated with melphalan / dexamethasone (MDex), 42 (31%) with bortezomib-based regimens, 14 (10%) underwent stem cell transplant (ASCT), 13 (10%) received thalidomide-based regimens, and the remaining patients received treatment for IgM clones or high-dose dexamethasone alone. After a median follow-up of living patients of 51 months, 23 patients (17%) died. Survival at 5 years was 82%. Twelve patients (52%) died a cardiac death (heart failure in 8 cases, sudden death in 4), after having developed cardiac involvement. All of them had baseline dFLC >100 mg/L. In these subjects the median NT-proBNP concentration at last assessment was 2401 ng/L, with a median 1646% increase compared to baseline. Of them 7 had failed to respond to frontline therapy, and the remaining had progressed after an initial partial response (PR, 3 cases) or very good partial response (VGPR, 2 cases). Eight patients (35%) died of liver failure. Six satisfied the criteria for liver involvement at baseline, and 2 developed hepatic amyloidosis during the follow-up, but had elevated ALP at baseline (1.3 and 1.4 times the u.r.l., respectively). Among them, 5 were non-responders to first-line therapy, and 3 had relapsed after PR (1) and VGPR (2). One patient died due to GI bleeding during ASCT. In the remaining 2 patients the causes of death were not directly related to the disease: myelodysplasia (5.9 years after having achieved VGPR with 6 cycles of MDex), and colorectal cancer (6.5 years after diagnosis). Only the two deaths that were not disease-related occurred in patients who presented with normal ALP and dFLC <100 mg/L (Figure). Elevated ALP (HR 5.11, P<0.001) and dFLC (HR 4.79, P<0.001) were independent prognostic factors at multivariate analysis. Conclusion. This is the first study specifically addressing the outcome of patients with non-cardiac AL amyloidosis. Cardiac dysfunction after development of heart involvement remains the first cause of death also in patients who do not have cardiac involvement at diagnosis. Notably, fatal cardiac amyloidosis occurred only in patients in whom dFLC was >100 mg/L at diagnosis. Progressive liver involvement emerges as a significant cause of death in Stage I AL patients, and is predicted by elevated ALP. Patients with non-cardiac AL who have high dFLC and/or ALP should be treated aggressively to prevent the onset of terminal organ damage. Figure Figure. Survival of patients with non-cardiac AL amyloidosis according to baseline dFLC and alkaline phosphatase Disclosures Merlini: Millennium Takeda: Honoraria.

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

Blood ◽

10.1182/blood.v110.11.1500.1500 ◽

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.

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