Arnt V. Kristen

Longitudinal left ventricular function for prediction of survival in systemic light-chain amyloidosis: incremental value compared with clinical and biochemical markers.

OBJECTIVES The aim of the study was to determine whether longitudinal left ventricular (LV) function provides prognostic information in a large cohort of patients with systemic light-chain (AL) amyloidosis. BACKGROUND AL amyloidosis is associated with a high incidence of cardiovascular events. Reduced myocardial longitudinal function is one of the hallmarks of myocardial involvement in this rare disease. METHODS Two hundred six consecutive patients with biopsy-proven AL amyloidosis were investigated in this prospective observational study. Echocardiographic imaging parameters, mean tissue Doppler-derived longitudinal strain (LS), and two-dimensional global longitudinal strain (2D-GLS) of the LV, cardiac serological biomarkers, and comprehensive clinical disease characteristics were assessed. The primary endpoint was all-cause mortality or heart transplantation. RESULTS After a median follow-up of 1207 days, LS and 2D-GLS were significant predictors of survival in AL amyloidosis. The cutoff values discriminating survivors from nonsurvivors were -10.65% for LS and -11.78% for 2D-GLS. In a multivariable echocardiographic Cox model, only diastolic dysfunction and 2D-GLS remained as independent predictors of survival. In comprehensive clinical models, 2D-GLS (p < 0.0001), diastolic dysfunction (p < 0.01), the pathologic free light chains (p < 0.05), cardiac troponin-T (cTnT) (p < 0.01), and the Karnofsky index (p < 0.001) remained as independent predictors. 2D-GLS delineated a superior prognostic value compared with that derived from pathologic free light chains or cTnT in patients evaluated before firstline chemotherapy (n = 113; p < 0.0001), and remained the only independent predictor besides the Karnofsky index in subjects with preserved LV ejection fraction (≥50%; n = 127; p < 0.01). LS and 2D-GLS both offered significant incremental information (p < 0.001) for the assessment of outcome compared with clinical variables (age, Karnofsky index, and New York Heart Association functional class) and serological biomarkers. CONCLUSIONS In the largest serial investigation reported so far, reduced LV longitudinal function served as an independent predictor of survival in AL amyloidosis and offered incremental information beyond standard clinical and serological parameters.

Prophylactic implantation of cardioverter-defibrillator in patients with severe cardiac amyloidosis and high risk for sudden cardiac death

BACKGROUND Cardiac light-chain amyloidosis carries a high risk for death predominantly from progressive cardiomyopathy or sudden death (SCD). Independent risk factors for SCD are syncope and complex nonsustained ventricular arrhythmias. OBJECTIVE The purpose of this study was to test whether prophylactic placement of an implantable cardioverter-defibrillator (ICD) reduces SCD in patients with cardiac amyloidosis. METHODS Nineteen patients with histologically proven cardiac amyloidosis and a history of syncope and/or ventricular extra beats (Lown grade IVa or higher) received an ICD. RESULTS During a mean follow-up of 811 +/- 151 days, two patients with sustained ventricular tachyarrhythmias were successfully treated by the ICD. Two patients underwent heart transplantation, and seven patients died due to electromechanical dissociation (n = 6) or glioblastoma (n = 1). Nonsurvivors more often showed progression of left ventricular wall thickness, low-voltage pattern, ventricular arrhythmias (Lown grade IVa or higher), and higher N-terminal pro-brain natriuretic peptide levels than did survivors. Bradycardias requiring ventricular pacing (VVI 40/min <1%, DDD 60/min 6% +/- 1%) occurred only rarely. CONCLUSION Patients with cardiac amyloidosis predominantly die as a result of electromechanical dissociation and other diagnoses not amenable to ICD therapy. Selected patients with cardiac amyloidosis may benefit from ICD placement. Better predictors of arrhythmia-associated SCD and randomized trials are required to elucidate the impact of ICD placement in high-risk patients with cardiac amyloidosis.

Assessment of disease severity and outcome in patients with systemic light-chain amyloidosis by the high-sensitivity troponin T assay

Cardiac biomarkers provide prognostic information in light-chain amyloidosis (AL). Thus, a novel high-sensitivity cardiac troponin T (hs-TnT) assay may improve risk stratification. hs-TnT was assessed in 163 patients. Blood levels were higher with cardiac than renal or other organ involvement and were related to the severity of cardiac involvement. Increased sensitivity was not associated with survival benefit. Forty-seven patients died during follow-up (22.3 ± 1.0 months). Nonsurvivors had higher hs-TnT than survivors. Outcome was worse if hs-TnT more than or equal to 50 ng/L and best less than 3 ng/L. Survival of patients with hs-TnT 3 to 14 ng/L did not differ from patients with moderately increased hs-TnT (14-50 ng/L), but was worse if interventricular septum was more than or equal to 15 mm. Discrimination according to the Mayo staging system was only achieved by the use of the hs-TnT assay, but not by the fourth-generation troponin T assay. Multivariate analysis revealed hs-TnT, NT-proBNP, and left ventricular impairment as independent risk factors for survival. hs-TnT and NT-proBNP predicted survival, even after exclusion of patients with impaired renal function. Plasma levels of the hs-TnT assay are associated with the clinical, morphologic, and functional severity of cardiac AL amyloidosis and could provide useful information for clinicians on cardiac involvement and outcome.

Non‐invasive predictors of survival in cardiac amyloidosis

Patients with cardiac amyloidosis (CA) have increased mortality.

Treatment with intravenous melphalan and dexamethasone is not able to overcome the poor prognosis of patients with newly diagnosed systemic light chain amyloidosis and severe cardiac involvement

Treatment with oral melphalan and dexamethasone (M-Dex) was reported to be effective and feasible in patients with systemic light chain amyloidosis (AL) not eligible for high-dose melphalan. We report on 61 patients with advanced AL who were treated with intravenous M-Dex as first-line therapy. Estimated median overall survival (OS) was 17.5 months. Seventeen patients (28%) died within 3 months, mostly of disease-related complications. In addition, nonhematologic toxicity of Common Terminology Criteria grade 3 or 4 was observed in 20 patients, whereas hematologic toxicity was low. Twenty-seven patients (44%) had hematologic response, including complete in 7 patients (11%) and partial remission in 20 patients (33%). Organ response was observed in 15 patients (25%). The amount of the involved free light chains in serum and Karnofsky Index at diagnosis significantly influenced OS. Plasma levels of the cardiac biomarkers before start of treatment and their increase after the third M-Dex cycle also were strong negative predictors of OS. These parameters might help to identify patients who will not benefit from M-Dex chemotherapy.

High-dose melphalan with autologous stem cell transplantation after VAD induction chemotherapy for treatment of amyloid light chain amyloidosis: a single centre prospective phase II study

Amyloid light chain (AL) amyloidosis is the result of a clonal plasma cell expansion, in which monoclonal light chains transform to amyloid deposit in various tissues and can lead to organ dysfunction and organ failure. The median survival of patients with AL amyloidosis without therapy is 10–14 months. With high‐dose melphalan (HDM) and autologous stem cell transplantation (ASCT), haematological and clinical remission rates of up to 50% of treated patients have been reported from phase II studies. HDM followed by ASCT appears to prolong survival in patients, if haematological remission can be reached. In this phase II study, we evaluated vincristine, adriamycin and dexamethasone (VAD) as induction chemotherapy prior to stem cell mobilization and HDM with ASCT. The regimen was, in general, feasible in patients with AL amyloidosis, but VAD chemotherapy had a considerable World Health Organization (WHO) grade III–IV toxicity (25%) and mortality (7%) rate. VAD pretreatment did not interfere with stem cell mobilization and HDM with ASCT was possible in 86% of patients. The overall treatment efficacy was comparable with reported results of HDM and ASCT without preceding chemotherapy. We could not show an additional benefit of VAD induction in terms of increasing haematological response rate; however the 13% mortality rate after HDM and ASCT in our series was lower than the previous report.

MR-relaxometry of myocardial tissue : Significant elevation of T1 and T2 relaxation times in cardiac amyloidosis

Objective:This study evaluates if MR-relaxometry of myocardial tissue reveals significant differences in cardiac amyloidosis (CA) compared with patients with systemic amyloidosis but without cardiac involvement (NCA) and a healthy control group. Therefore, we measured T1 and T2 relaxation times (RT) of the left ventricular myocardium with magnetic resonance imaging at 1.5 T. Material and Methods:Nineteen consecutive patients (14 males, 5 females; mean age, 59 ± 6.1 years) with histologically proven CA were evaluated. T1-RT and T2-RT were measured by using a saturation-recovery TurboFLASH sequence and a HASTE sequence, respectively. Additionally, morphologic and functional data were acquired. Results were compared with patients with systemic amyloidosis but without cardiac involvement (NCA; 5 males, 4 females, 48.9 ± 15.4 years) and 10 healthy, age-matched control subjects (5 males, 5 females, 60.4 ± 6.4 years). Results:MR-relaxometry revealed a significant elevation of T1-RT of the left ventricular myocardium in CA-patients compared with that in NCA-patients and the age-matched control group [mean ± SD (95% CI) 1340 ± 81 (1303–1376) msec, 1213 ± 79 (1160–1266) msec, 1146 ± 71 (1096–1196) msec, respectively; CA vs. control, P < 0.0001; CA vs. NCA:, P < 0.0003; NCA vs. control, P = 0.07]. T2-RT showed a marginal but significant increase in CA-patients compared with NCA-patients and the control group [mean ± SD (95% CI) 81 ± 12 (76–86) msec, 71 ± 11 (64–79) msec, 72 ± 9 (65–79) msec, respectively; CA vs. control, P = 0.04; CA vs. NCA, P = 0.04; NCA vs. control, P = 0.91]. T1-RT was best suited to discriminate between the groups as shown by logistic regression. A cut-off value of ≥1273 milliseconds for T1-RT was defined using receiver–operator characteristics-analysis to establish the diagnosis of CA with a high sensitivity (84%) and specificity (>89%). Conclusions:Measurement of T1 and T2 RT is a novel approach for noninvasive evaluation of CA. MR-relaxometry might improve diagnostic reliability of magnetic resonance imaging for evaluation of cardiac involvement in systemic amyloidosis.

In vivo detection of nerve injury in familial amyloid polyneuropathy by magnetic resonance neurography

See Morrow and Reilly (doi:10.1093/awu396) for a scientific commentary on this article. Transthyretin familial amyloid polyneuropathy is a rare, autosomal-dominant multisystem disorder. Kollmer et al. show that high-resolution MR-neurography can quantify and localize lower limb nerve injury in vivo, both in symptomatic patients and in asymptomatic mutation carriers. Lesions appear at thigh-level and are predominantly proximal, although symptoms start and prevail distally.

Late enhancement in cardiac amyloidosis: correlation of MRI enhancement pattern with histopathological findings

Late enhancement (LE) in cardiac magnetic resonance imaging (MRI) is a characteristic finding in patients with cardiac amyloidosis (CA) but the histomorphological explanation has not been clarified yet. Five patients with CA were evaluated by MRI prior to heart transplantation. This consisted of morphological, volumetric, and functional data, including LE analysis. For LE analysis, left ventricular (LV) short-axis sections from basal, midventricular, and apical positions were divided into 12 segments resulting in a 36-segment model. Each segment was differentiated by subendocardial, midmural, and subepicardial localization. Histological amyloid and collagenous fiber deposition was correlated with LE in corresponding MRI slides. LE was visualized in 103/180 (57.2%) predominantly subendocardial segments. Histological analysis of amyloid deposition was (peri-)vascular (n = 5), diffuse interstitial (n = 3) and/or nodular (n = 4). Extent of fibrosis was moderate to severe. Cytoplasmatic vacuolization and decline of myofibrils was seen in all patients. Fibrosis was significantly associated with LE in subendocardial and midmural localizations (p<0.05), whereas the extent of amyloid deposition was not associated with LE findings in any region. LE seems to be associated with fibrosis due to ischemia of cardiomyocytes by small vessel amyloid deposition rather than with amyloid deposition in CA, suggesting that amyloid deposition might be present prior to LE detection.

Prevalence of germline mutations in the TTR gene in a consecutive series of surgical pathology specimens with ATTR amyloid.

Transthyretin-derived amyloidosis (ATTR) amyloidosis is the third most prevalent amyloid type in surgical pathology and may occur as a hereditary disease with germline mutations in the TTR gene or as senile systemic amyloidosis (SSA) without mutations. Distinction between hereditary ATTR amyloidosis and SSA is of central importance, as the former necessitates genetic counseling and can be treated by liver transplantation. However, little is known about the prevalence of hereditary ATTR amyloidosis in surgical pathology specimens. We have examined the distribution of hereditary ATTR amyloidosis and SSA in a consecutive series of surgical pathology specimens with histologically and immunohistochemically confirmed ATTR amyloid. Thirty-three consecutive patients were retrieved from the Amyloid Registry of the Charité University Hospital. Genomic DNA was extracted from formalin-fixed and paraffin-embedded tissue or patient blood and examined by DNA sequencing. ATTR amyloid was found in the gastrointestinal tract, endomyocardium, peripheral nerve, carpal tunnel ligament, synovia, breast, and testicle. Amyloid fibrils were present as interstitial and vascular deposits, as evidenced by Congo red staining. TTR gene mutations were detected in 12 of 30 patients, with p.Val30Met being the most prevalent (5 patients). Furthermore, 2 novel mutations (p.Asp39Val and p.Glu54Asp) were found. In patients carrying a mutation, ATTR amyloid was found in the gastrointestinal tract, myocardium, nerve, and testicles. To conclude, the hereditary form of ATTR amyloid seems to be more common in elderly patients than previously thought. It is, therefore, important to genetically test every patient when diagnosing ATTR amyloidosis.