Cardiac [99mTc]Tc-hydroxydiphosphonate uptake on bone scintigraphy in patients with hereditary transthyretin amyloidosis: an early follow-up marker?

PURPOSE: There is a need for early quantitative markers of potential treatment response in patients with hereditary transthyretin (ATTRv) amyloidosis to guide therapy. This study aims to evaluate changes in cardiac tracer uptake on bone scintigraphy in ATTRv amyloidosis patients on different treatments. METHODS: In this retrospective cohort study, outcomes of 20 patients treated with the transthyretin (TTR) gene silencer patisiran were compared to 12 patients treated with a TTR-stabilizer. Changes in NYHA class, cardiac biomarkers in serum, wall thickness, and diastolic parameters on echocardiography and NYHA class during treatment were evaluated. RESULTS: Median heart/whole-body (H/WB) ratio on bone scintigraphy decreased from 4.84 [4.00 to 5.31] to 4.16 [3.66 to 4.81] (p < .001) in patients treated with patisiran for 29 [15-34] months. No changes in the other follow-up parameters were observed. In patients treated with a TTR-stabilizer for 24 [20 to 30] months, H/WB ratio increased from 4.46 [3.24 to 5.13] to 4.96 [ 3.39 to 5.80] (p = .010), and troponin T increased from 19.5 [9.3 to 34.0] ng/L to 20.0 [11.8 to 47.8] ng/L (p = .025). All other parameters did not change during treatment with a TTR-stabilizer. CONCLUSION: A change in cardiac tracer uptake on bone scintigraphy may be an early marker of treatment-specific response or disease progression in ATTRv amyloidosis patients.

Nuclear imaging in cardiac amyloidosis.

Amyloidosis is a disease characterized by depositions of amyloid in organs and tissues. It can be localized (in just one organ) or systemic. Cardiac amyloidosis is a debilitating disease and can lead to arrhythmias, deterioration of heart function and even sudden death. We reviewed PubMed/Medline, without time constraints, on the different nuclear imaging modalities that are used to visualize myocardial amyloid involvement. Several SPECT tracers have been used for this purpose. The results with these tracers in the evaluation of myocardial amyloidosis and their mechanisms of action are described. Most clinical evidence was found for the use of (123)I-MIBG. Myocardial defects in MIBG activity seem to correlate well with impaired cardiac sympathetic nerve endings due to amyloid deposits. (123)I-MIBG is an attractive option for objective evaluation of cardiac sympathetic level and may play an important role in the indirect measurement of the effect of amyloid myocardial infiltration. Other, less sensitive, options are (99m)Tc-aprotinin for imaging amyloid deposits and perhaps (99m)Tc-labelled phosphate derivatives, especially in the differential diagnosis of the aetiology of cardiac amyloidosis. PET tracers, despite the advantage of absolute quantification and higher resolution, are not yet well evaluated for the study of cardiac amyloidosis. Because of these advantages, there is still the need for further research in this field.

[AL-amyloidosis and its treatment by eliminating the precursor protein]. / AL-amyloïdose en de behandeling door eliminatie van het voorlopereiwit.

AL amyloidosis was diagnosed in 2 patients, women aged 61 and 43 respectively. The first patient, who had a nephrotic syndrome, died soon after diagnosis as the disease appeared to be already widespread. The second patient was still alive at the last follow-up, 17 years after diagnosis, because of effective elimination of her light chains by high-dose chemotherapy. AL amyloidosis is a rare, but severe, systemic disease with high mortality. Its aetiology lies in deregulated plasma cells producing excessive numbers of free immunoglobulin light chains. These light chains are the precursor proteins of amyloid fibrils. Amyloid fibrils are deposited extracellularly in tissue leading to organ dysfunction. Symptomatology is diverse, often non-specific, and generally not very well-known. Therefore, the diagnosis is often delayed for a long time. This is unfortunate, as high-dose chemotherapy targeted at elimination of the precursor protein considerably improves prognosis. However, this type of therapy can only be given in patients with limited and moderately progressive disease.

Therapeutic options in systemic AL amyloidosis.

Systemic amyloid light chain (AL) amyloidosis is a severe disease with unfavourable prognosis. Since the late 1970s different therapeutic modalities in AL amyloidosis have been investigated, trying to prolong survival. This review deals with the therapeutic modalities in AL amyloidosis to date, and highlights future perspectives.

Diagnostic and therapeutic approach of systemic amyloidosis.

Amyloidosis is a group of diseases, all characterised by deposition of protein fibrils with a beta-sheet structure. This structure generates affinity of amyloid for Congo red dye and is resistant to proteolysis. Three types of systemic amyloidosis are important for the clinician: AA (related to underlying chronic inflammation), AL (related to underlying monoclonal light chain production) and ATTR amyloidosis (related to old age or underlying hereditary mutations of transthyretin). Signs and symptoms vary considerably among the three types and the choice of treatment differs completely. A stepwise approach in diagnosis and therapy is presented. When amyloidosis is suspected the first step is histological proof of amyloid and the second is proof of systemic involvement. The next two steps are determination of the type of amyloid followed by detection of the precursor protein. The fifth step is a thoughtful clinical evaluation, necessary for assessment of prognosis and therapy. Subsequently, the choice of therapy is based on the 'precursor-product' concept. In the final step, the effects of therapy on the underlying disease as well as on the amyloidosis are assessed during follow-up. In this evaluation serum amyloid P component (SAP) scintigraphy helps to show organ involvement and therapy response.

Improvement of lipid profile is accompanied by atheroprotective alterations in high-density lipoprotein composition upon tumor necrosis factor blockade: a prospective cohort study in ankylosing spondylitis.

OBJECTIVE: Cardiovascular mortality is increased in ankylosing spondylitis (AS), and inflammation plays an important role. Inflammation deteriorates the lipid profile and alters high-density lipoprotein cholesterol (HDL-c) composition, reflected by increased concentrations of serum amyloid A (SAA) within the particle. Anti-tumor necrosis factor (anti-TNF) treatment may improve these parameters. We therefore undertook the present study to investigate the effects of etanercept on lipid profile and HDL composition in AS. METHODS: In 92 AS patients, lipid levels and their association with the inflammation markers C-reactive protein (CRP), erythrocyte sedimentation rate, and SAA were evaluated serially during 3 months of etanercept treatment. HDL composition and its relationship to inflammation markers was determined in a subgroup of patients, using surface-enhanced laser desorption/ionization time-of-flight analysis. RESULTS: With anti-TNF treatment, levels of all parameters of inflammation decreased significantly, whereas total cholesterol, HDL-c, and apolipoprotein A-I (Apo A-I) levels increased significantly. This resulted in a better total cholesterol:HDL-c ratio (from 3.9 to 3.7) (although the difference was not statistically significant), and an improved Apo B:Apo A-I ratio, which decreased by 7.5% over time (P=0.008). In general, increases in levels of all lipid parameters were associated with reductions in inflammatory activity. In addition, SAA was present at high levels within HDL particles from AS patients with increased CRP levels and disappeared during treatment, in parallel with declining plasma levels of SAA. CONCLUSION: Our results show for the first time that during anti-TNF therapy for AS, along with favorable changes in the lipid profile, HDL composition is actually altered whereby SAA disappears from the HDL particle, increasing its atheroprotective ability. These findings demonstrate the importance of understanding the role of functional characteristics of HDL-c in cardiovascular diseases related to chronic inflammatory conditions.

Heart rate variability as a predictor of mortality in patients with AA and AL amyloidosis.

AIMS: Patients with AA and AL amyloidosis have a limited life-expectancy. The aim of this study was to investigate whether heart rate variability can predict mortality in these patients. METHODS AND RESULTS: Twenty-two recently diagnosed patients with AA and 23 patients with AL amyloidosis were included. Fifteen patients (5 AA, 10 AL) died within 1 year. Twenty-four hour Holter recording was performed to quantify the mean of all normal to normal RR-intervals (mean NN) and the standard deviation of all normal to normal RR-intervals (SDNN). The SDNN predicted 1-year mortality in the total group of patients with amyloidosis. The median SDNN was 73 ms. In patients with an SDNN < or =73 ms, the risk of dying within 1 year was found to have increased 3.5-fold (P=0.0036; 95% CI 1.1-11.0). An SDNN < or =50 ms, a predictor of mortality in other patient groups, increased the risk of dying within 1 year 22-fold (P=0.0001; 95% CI 5.4-90.4). In contrast to patients with AA amyloidosis, in the subgroup analysis of patients with AL amyloidosis the SDNN remained a predictive parameter (SDNN < or =50 ms: risk ratio 11.5, 95% CI 2.4-56.2, P=0.0025). CONCLUSION: The SDNN is a strong predictor of short-term mortality in patients with AL amyloidosis.

Screening for amyloid in subcutaneous fat tissue of Egyptian patients with rheumatoid arthritis: clinical and laboratory characteristics.

OBJECTIVE: To screen for amyloid and to assess associated clinical and laboratory characteristics in Egyptian patients with rheumatoid arthritis (RA). METHODS: Abdominal subcutaneous fat aspirates were consecutively collected from 112 patients (103 women, nine men) having RA for five years or more. To detect amyloid, fat smears were stained with Congo red and the concentration of amyloid A protein in fat tissue was measured. Clinical, radiological, and laboratory characteristics of the patients were assessed. RESULTS: Amyloid was detected in eight (7%) of the fat smears stained with Congo red. Compared with the Congo red stain, the sensitivity for detecting amyloid by measurement of amyloid A protein in fat tissue was 75% and the specificity was 100%. The amount of amyloid found was small for both methods. The median disease duration of the eight amyloid patients was significantly longer (17 years) than that of the non-amyloid patients (10 years). Bronchopulmonary disease and constipation were more common, whereas proteinuria and chronic renal insufficiency were not. The number of swollen joints and the number of red blood cells were significantly lower in the amyloid group. CONCLUSIONS: Quantification of amyloid A protein and staining with Congo red are strongly concordant methods of screening for amyloid in fat tissue. The prevalence of amyloid in Egyptian patients with RA is 7%. Proteinuria is not a discriminating feature, whereas long disease duration, constipation, bronchopulmonary symptoms, and a moderate to low number of red blood cells may help to identify the arthritic patients with amyloid.