Cardiac amyloidosis

Systemic amyloidosis comprises an uncommon group of disorders caused by the extracellular deposition of misfolded proteins in various organs. Cardiac amyloid deposition, causing an infiltrative/restrictive cardiomyopathy, is a frequent feature of amyloidosis and a major determinant of survival. It may be the presenting feature of the disease or may be identified while investigating a patient presenting with other organ involvement. The need for a high index of suspicion and the critical importance of precise biochemical typing of the amyloid deposits is paramount in light of recent therapeutic advances that can significantly improve prognosis. Most cases of cardiac amyloidosis are of either transthyretin type, which may be acquired in older individuals or inherited in younger patients, or acquired monoclonal immunoglobulin light chain (AL) type. This article aims to review recent developments in diagnosis and management of cardiac amyloidosis

A case report in cardiovascular magnetic resonance: the contrast agent matters in amyloid

BACKGROUND: Cardiac amyloidosis is a progressive but underdiagnosed and underappreciated cause of heart failure. In the last few years, cardiovascular magnetic resonance (CMR) has become the gold standard for non invasive diagnosis of cardiac amyloidosis with the characteristic subendocardial late gadolinium enhancement. CASE PRESENTATION: We describe a case of a patient who, in the process of aligning protocols for a trial between different centers, had a paired study with two different contrast agents, Dotarem® and MultiHance®. MultiHance® surprisingly failed to demonstrate the characteristic imaging pattern, showing only non specific late gadolinium enhancement at the inferior right ventricular insertion point and different myocardial extracellular volume fraction compared to the one obtained with Dotarem®. MultiHance® is used by many centres, because its partial blood protein binding is a strength for MR angiography, but late gadolinium enhancement, particularly non-ischemic, appears to be compromised. CONCLUSIONS: This case report suggests that contrast agents should be selected with caution, especially with new therapies lining up for amyloid and CMR being used as exploratory end point in clinical trials

Cardiovascular magnetic resonance-guided right heart catheterization in a conventional CMR environment - predictors of procedure success and duration in pulmonary artery hypertension

Background Cardiovascular magnetic resonance imaging (CMR) is valuable for the investigation and management of pulmonary artery hypertension (PAH), but the direct measurement of pulmonary hemodynamics by right heart catheterization is still necessary. CMR-guided right heart catheterization (CMR-RHC) combines the benefits of CMR and invasive cardiac catheterization, but its feasibility in patients with acquired PAH has not been established. The aims of this study are to: (1) demonstrate the feasibility of CMR-RHC in patients being assessed for PAH in a conventional diagnostic CMR scanner room; (2) determine the predictors of (i) procedure duration, and (ii) procedural failure or technical difficulty as determined by the adjunctive need for a guidewire. Methods Fifty patients investigated for suspected or known PH underwent CMR-RHC. Durations of separate procedural components were recorded, including time taken to pass the catheter from the femoral vein to a stable wedge position (procedure time) and total time the patient spent in the CMR department (department time). Associations between procedural failure/guidewire usage and hemodynamic/CMR measures were assessed using logistic regression. Relationships between procedure times and hemodynamic/CMR measures were evaluated using Spearman’s correlation coefficient. Results A full CMR-RHC study was successfully completed in 47 (94%) patients. CMR-conditional guidewires were used in 6 (12%) patients. Metrics associated with guidewire use/procedural failure were higher mean pulmonary artery (PA) pressures (mPAP: OR = 1.125, p = 0.018), right heart dilatation (right ventricular (RV) end-systolic volume (RVESV): OR = 1.028, p = 0.018), RV hypertrophy (OR = 1.050, p = 0.0067) and RV ejection fraction (EF) (OR = 0.914, p = 0.014). Median catheter and department times were 3.6 (2.0–7.7) minutes and 60.0 (54.0–68.5) minutes, respectively. All procedure times became significantly shorter with increasing procedural experience (p < 0.05). Catheterization time was also associated with PH severity (RV systolic pressure: rho = 0.46, p = 0.0013) and increasing RV end-systolic volume (RVESV: rho = 0.41, p = 0.0043), hypertrophy (rho = 0.43, p = 0.0025) and dysfunction (RVEF: rho = − 0.32, p = 0.031). Conclusions This study demonstrates that CMR-RHC using standard technology can be incorporated into routine clinical practice for the investigation of PAH. Procedural failure was rare but more likely in patients with severe PAH. Procedure time is clinically acceptable and increases with worsening PAH severity

A 24-year experience of autologous stem cell transplantation for light chain amyloidosis patients in the United Kingdom

Autologous stem cell transplantation (ASCT) is considered to be the best method to achieve deep haematological/organ responses and improve survival in selected patients with AL amyloidosis. This field has been led by US centres and is less utilised in Europe. The introduction of effective chemotherapy agents for AL prompted us to re‐evaluate UK outcomes of ASCT in affected patients. A total of 264 AL amyloidosis patients treated with an ASCT between 1994 and 2018 were identified. Patient baseline characteristics, transplant‐related mortality (TRM) and overall survival (OS) were analysed. The median OS post‐ASCT was 87 months [95% confidence interval (CI): 77–106 months]. The median time from ASCT to next treatment was 48 months (95% CI: 29–55 months). A haematological response was achieved in 94·8% of patients and was a strong predictor of time to next treatment [P < 0·0001, hazard ratio (HR) = 1·75, 95% CI = 1·35–2·28] and OS (P = 0·007, HR = 1·91, 95% CI = 1·19–3·07). Organ response was: cardiac (n = 28, 60·9%), renal (n = 101, 76%) and liver (n = 7, 13·5%). Overall TRM was 8·7%, with a significant reduction over time (1994–2000: 18·8%; 2001–2006: 13·6%; 2007–2012: 6·2%; 2013–2018: 1·1%). In conclusion, ASCT is significantly safer and remains a highly effective treatment with excellent long‐term survival; it should be more widely considered as a treatment option for systemic AL amyloidosis

Autologous stem cell transplantation vs bortezomib based chemotheraphy for the first‐line treatment of systemic light chain amyloidosis in the UK

OBJECTIVES: The benefit of autologous stem cell transplantation (ASCT) in the treatment of light chain (AL) amyloidosis requires re-evaluation in the modern era. This retrospective case-matched study compares ASCT to bortezomib for the treatment of patients with AL amyloidosis. METHODS: Newly diagnosed patients with AL amyloidosis treated with ASCT or bortezomib between 2001-2018 were identified. Patients were excluded if the time from diagnosis to treatment exceeded 12 months. Patients were matched on a 1:1 basis, using a propensity matched scoring approach. RESULTS: A total of 136 propensity-score matched patients were included (ASCT n= 68, bortezomib n=68). There was no significant difference in overall survival at two years (p=0.908, HR: 0.95, CI:0.41-2.20). For ASCT vs. bortezomib: overall haematological response rate at six months was 90.6% vs. 92.5%; organ response at 12 months: cardiac (70.0% vs. 54%, p>0.999), renal (74% vs.24%, p=0.463)) liver (21% vs. 22%, p=0.048); median progression free survival (50 vs. 42 months p=0.058, HR:0.61, CI:0.37-1.02) and time to next treatment (68 vs. 45 months, p=0.145, HR:0.61, CI:0.31-1.19). More patients required treatment in the bortezomib group compared to ASCT group at 24 months (41 vs. 23, Chi squared p=0.004) and 48 months (57 vs 41, Chi squared p= 0.004). CONCLUSIONS: This small retrospective study suggests that there is no clear survival advantage of ASCT over bortezomib therapy. A prospective randomised controlled trial evaluating ASCT in AL amyloidosis is critically needed

Impact of early response on outcomes in AL amyloidosis following treatment with frontline Bortezomib

The outcomes in systemic AL amyloidosis are dependent on the depth of haematologic response. However, there is limited data on the impact of the speed of response on outcomes. Here we report the impact of speed of response in a cohort of AL patients treated with upfront Bortezomib. Patients seen from February 2010 until August 2019 are included in the present analysis. 1194 & 1133 patients comprised the ITT and 1-month landmark cohorts. In the landmark cohort, 137 (11.5%), 270 (22.6%), 252 (21.1%) and 352 (31.1%) patients had a CR, VGPR, PR and NR at 1-month. Patients with ≥ VGPR at 1-month had significantly better survival (median not reached; at the end of 1, 2, 5,10 years, 87%/92%, 83%/87%, 68%/72% and 63%/58% of patients in CR/VGPR, respectively, were alive) compared to those with a PR (median OS 60 months) or NR (median OS 32 months) (p  20 mg/l (p = 0.005). Reaching ≥ VGPR at 1-month significantly improved survival in all Mayo disease stages. In conclusion, patients achieving an early deep haematologic response have a significantly superior survival irrespective of cardiac involvement

Reduction in CMR Derived Extracellular Volume With Patisiran Indicates Cardiac Amyloid Regression

OBJECTIVES: The purpose of this study was to determine the effect of patisiran on the cardiac amyloid load as measured by cardiac magnetic resonance and extracellular volume (ECV) mapping in cases of transthyretin cardiomyopathy (ATTR-CM). BACKGROUND: Administration of patisiran, a TTR-specific small interfering RNA (siRNA), has been shown to benefit neuropathy in patients with hereditary ATTR amyloidosis, but its effect on ATTR-CM remains uncertain. METHODS: Patisiran was administered to 16 patients with hereditary ATTR-CM who underwent assessment protocols at the UK National Amyloidosis Centre. Twelve of those patients concomitantly received diflunisal as a "TTR-stabilizing" drug. Patients underwent serial monitoring using cardiac magnetic resonance, echocardiography, cardiac biomarkers, bone scintigraphy, and 6-min walk tests (6MWTs). Findings of amyloid types and extracellular volumes were compared with those of 16 patients who were retrospectively matched based on cardiac magnetic resonance results. RESULTS: Patisiran was well tolerated. Median serum TTR knockdown among treated patients was 86% (interquartile range [IQR]: 82% to 90%). A total of 82% of cases showed >80% knockdown. Patisiran therapy was typically associated with a reduction in ECV (adjusted mean difference between groups: -6.2% [95% confidence interval [CI]: -9.5% to -3.0%]; p = 0.001) accompanied by a fall in N-terminal pro-B-type natriuretic peptide concentrations (adjusted mean difference between groups: -1,342 ng/l [95% CI: -2,364 to -322]; p = 0.012); an increase in 6MWT distances (adjusted mean differences between groups: 169 m [95% CI: 57 to 2,80]; p = 0.004) after 12 months of therapy; and a median reduction in cardiac uptake by bone scintigraphy of 19.6% (IQR: 9.8% to 27.1%). CONCLUSIONS: Reductions in ECV by cardiac magnetic resonance provided evidence for ATTR cardiac amyloid regression in a proportion of patients receiving patisiran

Haematologic responses and survival do not significantly decrease with subsequent lines of therapy in systemic immunoglobulin light chain amyloidosis: results from an analysis of real-world longitudinal data

Systemic immunoglobulin light chain amyloidosis (AL) is an incurable disorder, and the natural history is incompletely understood. In this study, we describe its natural history based on an analysis of real-world longitudinal data. All patients seen at the National Amyloidosis Centre, UK, between February 2010 and August 2019 and treated with up-front bortezomib are included. In all, 1 276 patients received the first-line treatment; 259, 85, and 32 patients received second, third, and fourth treatment lines, respectively. Among patients requiring further treatment after the first line, 77·2% started the second line within two years of the first line; 50·5%, 50·6%, 40·1% and 40·6% of patients had achieved at least very good partial response after the first, second, third and fourth treatment lines. Median overall survival (OS) from first, second, third and fourth lines was 45 months, 56 months, 37 months and not reached, respectively (P = 0·109). In summary, although relapses occur in AL amyloidosis, the outcomes and responses do not worsen with each subsequent relapse, making it attractive to design therapeutics with curative intent