Validation of the Boston University staging system in AL amyloidosis

Objectives: We aimed to externally validate Lilleness’ et al. Boston University (BU) prognostic score that replaced NT-proBNP with brain natriuretic peptide (BNP), which will allow centres without access to NT-proBNP to accurately stage and prognosticate AL amyloidosis.

Patients/methods: Forty-four were identified that had BNP, NTpro-BNP and TnI taken simultaneously, with a mean follow up of 7.3?years. Median age of the 44 patients was 67?years and 27% were female, with 61% having cardiac involvement, and 61% having renal involvement.

Results: Using the BU BNP-based staging system, we identified 12/44 (27%) of patients as stage I, 18/44 (41%) of patients as stage II and 14/44 (31%) of patients as stage III. This correlated closely with stratification via the Mayo score, with only one patient miscategorised (97.7% agreement, k?=?0.98). Median overall survival for our BU stage I was not reached, stage II was 40?months and stage III was 5?months (long rank p?=?.0012). Mayo 2004 median overall survival was identical for stages I, II and III.

Conclusion: We have provided external validation of the BU staging system, a novel prognostic scoring system incorporating BNP, instead of NT-proBNP, for AL amyloidosis.     

Best use of cardiac biomarkers in patients with AL amyloidosis and renal failure

In AL amyloidosis prognosis depends on the severity of heart dysfunction which is best assessed by natriuretic peptides (BNP and NT-proBNP). However, their clearance relies on glomerular filtration rate (GFR) and their concentration increases with renal failure. We evaluated the diagnostic and prognostic performance of NT-proBNP and BNP in 248 patients with AL amyloidosis with different degrees of renal failure. Patients were grouped according to GFR. Group 1 comprised 109 patients with GFR ≥60 mL/min/1.73 m(2) , Group 2, 77 subjects with GFR <60 and ≥15 mL/min/1.73 m(2) , and Group 3, 62 patients with GFR <15 mL/min/1.73 m(2) . The ability of natriuretic peptides to detect heart involvement and to predict survival in the three groups was assessed. Decreasing eGFR required higher cutoffs of both NT-proBNP and BNP for detecting heart involvement and predicting survival. Both natriuretic peptides were independent prognostic markers in Groups 1 and 2, whereas in Group 3 only BNP independently predicted survival. Natriuretic peptides are powerful and useful markers of cardiac dysfunction and prognosis, provided that eGFR is considered in interpreting their clinical meaning. BNP should be preferred in patients with end-stage renal failure.     

Intramyocardial inflammation predicts adverse outcome in patients with cardiac AL amyloidosis

Aims

To evaluate the influence of endomyocardial biopsy (EMB)‐proven intramyocardial inflammation on mortality in patients with cardiac transthyretin amyloid (ATTR) or amyloid light‐chain (AL) amyloidosis.

Methods and results

We included 54 consecutive patients (mean age 68.83 ± 9.59 years; 45 men) with EMB‐proven cardiac amyloidosis. We followed up patients from first diagnostic biopsy to as long as 36 months (mean 11.5 ± 12 months) and compared their outcome with information on all‐cause mortality with or without proof of inflammation on EMB. Intramyocardial inflammation was assessed by quantitative immunohistology. Patients suffering from amyloidosis revealed a significant poor prognosis with proof of intramyocardial inflammation in contrast to those without inflammation (log‐rank P = 0.019). Re‐grouping of patients indicated AL amyloidosis to have a significant impact on all‐cause mortality (log‐rank P = 0.012). The detailed subgroup analysis showed that patients suffering from AL amyloidosis with intramyocardial inflammation have a significantly worse prognosis compared with AL amyloidosis without inflammation and ATTR with or without inflammation, respectively (log‐rank P = 0.014, contingency Fisher's exact test, P = 0.008).

Conclusion

Our study reports for the first time a high incidence (48.1%) of intramyocardial inflammation in a series of patients with EMB‐proven cardiac amyloidosis and could show that in patients with AL amyloidosis, intramyocardial inflammation correlated significantly with increased mortality. Our data have a direct clinical impact because one can hypothesize that additional immunomodulating/anti‐inflammatory treatment regimens in patients with biopsy‐proven inflammation of heart muscle tissue could be beneficial for patients suffering from cardiac AL amyloidosis.

     

Identification of prognostic markers in transthyretin and AL cardiac amyloidosis*

Abstract

Background: The prognosis of amyloidosis is known to depend heavily on cardiac function and may be improved by identifying patients at highest risk for adverse cardiac events.

Aims: Identify predictors of mortality in patients with cardiac light-chain amyloidosis (AL), hereditary transthyretin amyloidosis (m-TTR), or wild-type transthyretin amyloidosis (WT-TTR) to prompt physician to refer these patients to dedicated centers.

Methods and results: Observational study. About 266 patients referred for suspected cardiac amyloidosis (CA) in two French university centers were included. About 198 patients had CA (AL?=?118, m-TTR?=?57, and WT-TTR?=?23). Their median (25th–75th percentile) age, NT-proBNP left ventricular ejection fraction were, respectively, 68 years (59–76), 2339?pg mL^?1 (424–5974), and 60% (48–66). About 31% were in NYHA class III–IV. Interventricular septal thickness was greater in the m-TTR and WT-TTR groups than in the AL group (p?<?0.0001). Median follow-up in survivor was 26 months (15–44) and 87 (44%) patients died. By multivariate analysis, independent predictors of mortality for AL amyloidosis were the following: age, cardiac output and NT-proBNP; for TTR amyloidosis was: NT-proBNP. When all amyloidosis were combined NT-proBNP, low cardiac output and pericardial effusion were independently associated with mortality.

Conclusion: NT-proBNP is a strong prognosticator in the three types of cardiac amyloidosis. High NT-proBNP, low cardiac output, and pericardial effusion at the time of screening should prompt physician to refer the patients to amyloidosis referral center.     

A pilot study demonstrating cardiac uptake with 18F-florbetapir PET in AL amyloidosis patients with cardiac involvement

Abstract

¹⁸F-florbetapir is a promising tracer in amyloidosis. This study evaluates its use in patients with systemic AL amyloidosis (AL) before and after treatment as well as its serial utility in monitoring. Fifteen AL patients with cardiac involvement underwent ¹⁸F-florbetapir PET imaging and three patients underwent repeat imaging after chemotherapy. All patients had demonstrable cardiac uptake with ¹⁸F-florbetapir. Cardiac uptake appeared greater in chemotherapy-naïve vs. chemotherapy-established AL patients median (left ventricular retention index 0.21 vs. 0.14?min^?1, respectively) and greater in patients that had not achieved at least a partial haematological response (left ventricular retention index 0.2 vs. 0.14?min^?1, respectively). There was no interval difference in cardiac uptake and no correlation in cardiac uptake with cardiac biomarkers or serum free light chains. This is the largest study of ¹⁸F-florbetapir in patients with AL amyloidosis. It is the first study to include patients prior to starting chemotherapy and uniquely includes patients who underwent repeat imaging after chemotherapy. All patients had cardiac uptake with ¹⁸F-florbetapir, regardless of haematological or NT-proBNP response to chemotherapy. There was a suggestion that treatment-naïve patients may have higher cardiac uptake. Larger studies are required to establish the role of this tracer in screening patients with amyloidosis for cardiac involvement, discriminating between ATTR and AL amyloidosis, and in disease monitoring.     

Treatment of patients with advanced cardiac AL amyloidosis with oral melphalan, dexamethasone, and thalidomide

Patients with primary (AL) amyloidosis and heart failure have a very poor prognosis and cannot tolerate aggressive therapy, such as autologous stem cell transplantation and high-dose dexamethasone-based regimens. We prospectively treated 22 patients with advanced cardiac amyloidosis combining oral melphalan, thalidomide, and reduced intensity dexamethasone (MTD). Six patients died due to cardiac amyloidosis before completing cycle 3. Early death was associated with reduced ejection fraction. Eight patients achieved a hematological response and four achieved a durable improvement of cardiac dysfunction. Treatment with MTD is feasible in patients with advanced cardiac AL amyloidosis and effective in subjects with preserved systolic function. G.P. was partly supported by an investigator fellowship from Collegio Ghislieri, Pavia, Italy. Study supported in part by the Euramy Research Project funded by the European Community Sixth Framework Program     

Light-chain amyloidosis with renal involvement: renal outcomes and validation of two renal staging systems in the Chinese population

Abstract

Background: Renal involvement is one of the most common complications of light-chain (AL) amyloidosis. For evaluating renal prognosis, two staging systems for renal involvement have been proposed, one in 2014 and one in 2017. However, the two staging systems have not yet been compared and widely used in clinic.

Methods: A total of 76 patients with newly diagnosed AL amyloidosis and renal involvement proven by renal biopsy were included and followed up with an endpoint developing to dialysis. The renal outcome and two criteria were explored.

Results: We confirmed the prognostic value of the 2014 renal staging system based on estimated glomerular filtration rate (eGFR) (<50?ml/min/1.73?m²) and proteinuria (>5?g/day) at diagnosis (p?=?0.003). For the 2017 system, none of the patients progressed to dialysis in both stage 1 (24?h proteinuria to eGFR <30?mg/ml/min/1.73?m²) and stage 2 (24?h proteinuria to eGFR 30–99?mg/ml/min/1.73?m²). A significant difference in terms of requiring dialysis was seen only between stage 3 (24?h proteinuria to eGFR ≥100?mg/ml/min/1.73?m²) and the two other stages (p?=?0.008).

Conclusions: The prognostic value of the criteria based on eGFR and 24-hour proteinuria for predicting dialysis has been confirmed. These results might benefit guiding clinical treatment.     

Attitudes about when and how to treat patients with AL amyloidosis: an international survey

The aim of this survey was to describe the treatment decision making of expert physicians in when and how to treat patients with AL amyloidosis. Fifty amyloid expert physicians completed the survey. Autologous stem cell transplant (ASCT) was considered the first line therapy, if medically feasible, by 73% of the physicians. Excluding ASCT, cyclophosphamide-bortezomib-dexamethasone regimen was the preferred strategy by 72%. Depending on organ involvement, the goal for treatment was CR for 27–35% and very good partial response (VGPR) for 65–72%. In the absence of organ progression but rising FLC, the factors that most influenced when to reinstitute therapy included: dFLC at diagnosis (35.2%); how sick the patient was at diagnosis (24.1%); and time to FLC rise (18.5%). For patients who achieved CR after first-line, in the presence of cardiac/renal progression, 37/42% of providers would consider starting clone directed therapy without evidence of a clone. These data would imply that the current definitions of hematologic progression do not match clinical judgment, clinical experience and a comprehensive evaluation of patient status. These disparities challenge the ability to design therapeutic trials for patients with relapsed/refractory disease. A consensus statement with the definition and validation of new hematologic progression criteria is required.     

Amyloid cardiomyopathy in systemic non-hereditary amyloidosis. Clinical, echocardiographic and electrocardiographic findings in 30 patients with AA and 24 patients with AL amyloidosis

To underline the role of echocardiography in the detection ofcardiac involvement in patients with amyloidosis, physical examination,echocardiography and electrocardiography were performed in 30patients with AA amyloidosis (amyloid protein A, associatedwith chronic inflammatory disease, usually without cardiomyopathy)and 24 patients with AL amyloidosis (the immunoglobulin lightchain derived type, often associated with cardiomyopathy). Allpatients had histological confirmation of amyloidosis by rectalor subcutaneous abdominal fat biopsy. The combination of increased thickness of the left ventricularposterior wall and interventricular septum with a low voltageelectrocardiographic pattern is highly specific for cardiacamyloidosis and was found in 3/30 (10%) of the A A patientsand in 13/24 (54%) of the AL patients. The echocardiographic abnormalities were strongly related tothe degree of clinical heart disease, showing mildly or moderatelyincreased wall thickness in the early asymptomatic phase orsevere thickening and hypokinesia of the left ventricular posteriorwall and interventricular septum in clinically apparent cardiacdysfunction. Echocardiography appears to be a sensitive test for the detectionof cardiac involvement in amyloidosis, in symptomatic as wellas asymptomatic patients.     

心电图鉴别心肌淀粉样变与肥厚型心肌病

目的分析心肌淀粉样变及肥厚型心肌病患者心电图参数,获得能够简易快捷地诊断心肌淀粉样变及与肥厚型心肌病相鉴别的诊断流程。方法心肌淀粉样变患者(A组)、肥厚型心肌病患者(C组)、正常对照(B组)各30例,比较心电图参数特征,通过ROC曲线及logistic回归分析心电图参数的诊断价值并提出诊断流程。结果 A组肢体导联及左胸导联(V5、V6)低电压、假性梗死波及胸前导联R波递增不良比例较B组增高。诊断心肌淀粉样变(与B组鉴别):a VR导联QRS振幅(QRSa VR)联合PR间期减去P波时限(PR-P时限):敏感性96.30%,特异性96.67%,正确率96.49%。鉴别心肌淀粉样变与肥厚型心肌病:I导联QRS振幅(QRSI):界值0.46m V,敏感性90.00%,特异性96.67%;QRSa VR:界值0.41m V,敏感性93.33%,特异性93.33%;所有肢体导联QRS电压之和(6∑QRS):界值2.71m V,敏感性96.67%,特异性83.33%。结论心肌淀粉样变心电图多出现肢体导联及左胸导联低电压,假性梗死波,胸前导联R波递增不良等表现。QRSa VR联合PR-P时限可用于筛查心肌淀粉样变。QRSI、QRSa VR、6∑QRS可用于鉴别心肌淀粉样变和肥厚型心肌病。     

End-stage renal disease and dialysis in hereditary amyloidosis TTR V30M: presentation,survival and prognostic factors

Classical familial amyloid polyneuropathy may have a course with progressive renal impairment. We studied 62 patients (24 males, 38 females) with FAP, transthyretin variant V30M, and end-stage renal disease (ESRD) treated with hemodialysis, all referred to a single center over a period of 11 years. Clinical course, morbidity and survival after dialysis were analyzed. Patient's mean age at first dialysis was 51.5?±?10.7 years, and mean duration of neuropathy was 10.2?±?3.8 years. The most frequent form of presentation of FAP nephropathy was nephrotic proteinuria with renal dysfunction. In the year prior to dialysis, renal function declined rapidly, and fluid overload was the main indication to initiate treatment. The presence of decubitus ulcers, significant disability, venous catheter for definitive vascular access for long-term treatment, and permanent bladder catheter, were related to death during the first year of dialysis. The mean duration of renal replacement therapy was 21 months, with a 54.5% one year, and 38.4% two year treatment survival. However, when the duration of neurological symptoms at first dialysis exceeded 10 years, survival was significantly lower. Infections, (41% were decubitus ulcers with sepsis) were the cause of early, as well as late mortality. Early creation of vascular access for hemodialysis, surveillance of skin wounds, and intervention on neurogenic bladder are essential to improve the prognosis of ESRD in FAP.     

Rectal bleeding as a presenting symptom of AL amyloidosis and multiple myeloma

Amyloidosis of the gastrointestinal tract is a rare disease that presents with common, nonspecific signs and symptoms. It may affect any part of the gastrointestinal tract from mouth to anus. The clinical and endoscopic features are diverse and may mimic other diseases, such as inflammatory bowel disease, malignancy, ischemic colitis and, at times, collagenous colitis. We describe an uncommon case of rectal bleeding and anemia with polypoid lesions and ulcerations in the colon, as the presenting symptom of AL amyloidosis and light chain multiple myeloma.     

继发性肾淀粉样变的发病机制与治疗

继发于慢性炎性疾病等多种疾患的淀粉样变常累及肾脏，表现为大量蛋白尿，并可引起肾病综合征甚至功能衰竭，淀粉沉积物中的淀粉样A纤维以及淀粉样物促进因子，淀粉样P物质，载脂蛋白E，硫酸肝素蛋白多糖等成份参与了疾病的发生与发展，目前关于该疾患的药物治疗，如细胞毒类制剂，秋水仙碱，二甲亚砜的实验和临床研究日趋成熟，肾脏替代治疗的经验也日益丰富。     

心脏淀粉样变的心脏超声及心电图特点

目的：分析心脏淀粉样变患者的心脏超声及心电图特点,为临床医师早期识别和诊断心脏淀粉样变性提供帮助。方法：2003年7月～2011年10月我院结合临床及病理检查确诊心脏淀粉样变性患者20例,回顾性分析其超声心动图和心电图特点。结果：心脏超声检查所见：20例患者均表现室间隔[（15．67±3．60）mm]及左心室后壁向心性增厚[（15．73±3．54）mm]而左心室容积正常;所有患者均存在舒张功能不全;多数患者有左心房增大（19例,95％）,心内膜下心肌有颗粒样反光增强（17例,85％）,出现中一大量心包积液（11例,55％）。心电图表现为：20例患者心电图肢体导联的电压均较低,肢体导联低电压和假性梗死Q波的发生率分别为55％和45％。结论：不明原因心力衰竭的患者,如果心脏超声示心室肌肥厚且心室容积正常,伴心内膜下心肌内有颗粒样反光增强,而心电图又表现为肢体导联低电压或非梗死性Q波时,应考虑心脏淀粉样变性的可能性。应进一步行病理活检等检查,以利于早期诊断和治疗。     

A risk stratification for systemic immunoglobulin light-chain amyloidosis with renal involvement

Renal involvement is found in about 70% of patients with systemic immunoglobulin light-chain (AL) amyloidosis. However, there is no risk stratification system specialized for renal AL concerning patients’ survival. Galectin-3 (Gal-3) has been reported to portend poor prognosis in other renal diseases. We measured Gal-3 and several traditional risk biomarkers of AL in baseline samples from 253 consecutive patients diagnosed with renal AL. At baseline, Gal-3 [Hazard ratio (HR): 1·46; P = 0·033], high-sensitivity cardiac troponin T (hs-cTnT) (HR: 2·65; P < 0·001) and difference between involved and uninvolved free light chains (dFLC) (HR: 1·81; P = 0·001) were independent predictors of all-cause mortality. The cut-off points for Gal-3, hs-cTnT, and dFLC were 20·24 ng/ml, 0·026 ng/ml, and 75·89 mg/l, respectively. Patients were stratified into four stages by assigning a score of 1 for each of the three biomarkers above the cut-off point. The proportions of patients with disease stages 1, 2, 3 and 4 were 17·0%, 37·2%, 29·2% and 16·6%, and the median overall survival times from diagnosis were 100, 60, 29 and 15 months, respectively (P < 0·01). Higher level of Gal-3 is associated with increased risk for mortality, and the risk stratification based on Gal-3 is a reliable model for predicting mortality in AL amyloidosis with renal involvement.     

心脏淀粉样变患者的心电图和心脏超声特点

目的 总结心内膜心肌活检(EMB)证实原发型心脏淀粉样变(CA)患者的心电图和心脏超声特点,为临床医师能够早期识别和诊断CA提供帮助.方法 自2006年9月至2009年10月收治临床怀疑CA患者共20例(其中男性7例),平均年龄(50±12)岁,进行EMB检查.11例(55%)患者诊断为CA,血清和(或)尿检查示游离单克隆轻链(λ)明显升高,确诊为原发型CA.分析该11例心电图和心脏超声的特点.结果 心电图分析发现,11例患者的6个肢导联电压均较低,均值为0.33～0.51 mV,其中肢导联低电压和假性梗死波形发生率均为45%.心脏超声检查结果分析发现,11例患者室壁呈向心性增厚和左心室腔容积正常,绝大多数患者可见左心房扩大(10例,91%)、心肌内可见颗粒样强回声(9例,82%)、中至大量心包积液(7例,64%)以及左心室收缩功能受损(8例,73%).结论 对于临床原因不明的心力衰竭,心脏超声示向心性肥厚且左心室腔容积不大,伴心肌内颗粒样强回声或心包积液,而心电图示肢导联低电压或假性梗死波形者,高度疑似原发型CA的可能性,应进一步行EMB和血清(尿)生化检查,以便早期明确诊断和及时治疗.     

Tissue Doppler and strain imaging: a new tool for early detection of cardiac amyloidosis

Using traditional echocardiography, the diagnosis of cardiac amyloidosis (CA) is often only possible in advanced stage when recommended therapies may have adverse effects. The aim of our study was to evaluate whether additional information can be derived from Tissue and strain Doppler imaging (TDI and SDI). Forty patients with systemic amyloidosis and 24 healthy subjects underwent traditional, tissue and strain Doppler echocardiography. Patients were classified having CA if mean wall thickness (mT), was half of the sum septum and posterior wall thickness, was ≥12 mm. The following parameters were evaluated: peak early diastolic velocity (Em) as index of ventricular relaxation, mitral E-wave to Em ratio (E/Em) as index of left ventricular (LV) filling pressure and mean LV strain peak curves (mSt) as global long-axis contraction index. In non cardiac amyloidosis (NCA), both Em and mSt were lower than in age matched controls (p < 0.01, p < 0.05, respectively) and higher than in CA (p < 0.01 and p < 0.01, respectively). Both Em and mSt were related to mT (p < 0.001). A significant (p < 0.01) nonlinear relation was observed between plasma terminal of pro B-natriuretic peptide and mT, Em, E/Em and mSt. TDI and SDI are able to detect amyloid myocardial involvement in such an early stage that cannot be evidenced by using traditional echocardiography.     

Familial and primary (AL) cardiac amyloidosis: echocardiographically similar diseases with distinctly different clinical outcomes.

OBJECTIVE: To determine whether patients with myocardial amyloidosis due either to AL (primary) amyloid or familial amyloid have distinguishing echocardiographic or electrocardiographic features; and to compare the prevalence of heart failure and survival in the two types of amyloidosis in relation to echocardiographic findings. DESIGN: Blinded group comparison of randomly selected cases of cardiac amyloidosis. SETTING: International referral centre for amyloid research and treatment. PATIENTS: 36 patients with cardiac amyloid heart disease, of whom 12 had familial and 24 had primary AL amyloidosis. RESULTS: Familial and AL echocardiograms were morphologically indistinguishable, with similar left ventricular wall thickness, mean (SD) 15.4 (2.3) nu 15.8 (2.5) mm, respectively; right ventricular wall thickness was also similar between amyloid types: 9.6 (2.8) nu 9.7 (6.5) mm, respectively. Doppler indices of left and right ventricular function, left ventricular volume, and ejection fraction were also similar. Low voltage electrocardiograms (< 0.5 mV) were more common in the AL (16/24, 67%) than in the familial group (4/12, 25%), P < 0.05. The one year survival for familial and AL forms was 92% (11/12) nu 38% (6/24), respectively, with virtually all deaths due to cardiac causes. CONCLUSIONS: Although cardiac involvement is echocardiographically indistinguishable, cardiac mortality is very different between the two forms of amyloidosis. Preservation of electrocardiographic voltage in familial amyloidosis suggests that the particular biochemical characteristics of distinct types of amyloid fibril have different pathological effects on the myocardium. This distinction becomes critical in the evaluation, treatment, and management of patients who have a diagnosis within the spectrum of the protein deposition diseases.