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Amyloidosis

Immunoglobulin Light-chain Amyloidosis

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Neoplasms, Plasma Cell

Neoplasms by Histologic Type

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AL Amyloidosis

Participants in this cohort are individuals undergoing clinically indicated cardiac device implantation, such as pacemakers, ICDs, ILRs, or CRT-D/Ps. During the standard implantation procedure, chest wall fat tissue typically excised to create space for the device is collected for histopathological analysis to identify amyloid deposits. This study involves no additional intervention beyond the routine clinical care received by the patients.

As part of routine cardiac device implantation, chest wall fat tissue is collected for histopathological analysis. This tissue, which is typically discarded, will be used to identify amyloid deposits in high-risk cardiac patients. No additional surgical intervention is performed beyond the standard procedure for device implantation.

Chest Wall Fat Tissue Collection

Vasvi Singh, MD

Elizabeth Fulks, MS

This single-practice prospective cohort study aims to enhance the diagnosis of cardiac amyloidosis in high-risk patients undergoing standard cardiac device implantation. By analyzing chest wall fat tissue, which is usually discarded, we aim to determine the diagnostic yield of such biopsies for amyloidosis and to develop a predictive screening model based on clinical, lab, and imaging data. The study, running from December 2023 to December 2024, expects to enroll 100 patients and may provide a new, non-invasive diagnostic avenue for this condition.

The study targets a key gap in cardiac amyloidosis diagnosis by systematically evaluating the histopathological incidence of the disease using chest wall fat pad biopsies-tissue that is typically discarded during the implantation of cardiac devices like pacemakers, ICDs, and CRT-D/Ps. Standard surgical procedures are adhered to, ensuring minimal additional risk to patients. The collected tissue samples are analyzed by the HCA pathology laboratory to detect amyloid deposits, thereby potentially identifying amyloidosis in a non-invasive manner. In addition to the primary endpoint of histopathological diagnosis, the study retrospectively aims to validate a predictive model that incorporates a wide range of data to streamline the identification of patients at high risk for cardiac amyloidosis. Strict measures are in place to protect patient confidentiality and data security. By potentially improving diagnostic efficiency, this research could contribute to earlier detection and treatment strategies, thus improving patient outcomes for those at high risk of this life-threatening condition.

The biospecimens consist of chest wall fat tissue samples collected during cardiac device implantation procedures. This adipose tissue, typically excised to create space for the device, is preserved for histopathological analysis to detect amyloid deposits. The analysis of these samples is crucial for diagnosing cardiac amyloidosis in patients at high risk. The tissue will be handled and analyzed by the HCA pathology laboratory, following standard procedures to ensure the integrity of the samples and the accuracy of the diagnostic results.

Amyloidosis Incidence in High-Risk Cardiac Device Patients

Histopathological Incidence of Amyloidosis in High-Risk Patients Undergoing Cardiac Device Implantation

At present, the specifics of a data-sharing plan for individual participant data (IPD) from this study are under consideration. The study team intends to protect patient confidentiality and data integrity and will comply with all relevant regulations and guidelines for data sharing. Once a plan has been established, details about the nature of the data to be shared, the conditions for access, and the timing for data release will be provided.

The primary outcome measure is the histopathologic diagnosis of amyloidosis in chest wall fat tissue removed during cardiac device implantation

Retrospective development and validation of a predictive model using pre-procedural clinical, lab, and imaging data to identify patients at high risk for cardiac amyloidosis

Midwest Heart & Vascular Specialists

Symptoms and General Pathology

Arrhythmias, Cardiac

Death

Death, Sudden, Cardiac

Death, Sudden

Heart Arrest

Central Nervous System Depressants

All Drugs and Chemicals

Anesthetics

Anesthetics, Local

Eligible patients will undergo subcutaneous implantation of a cardiac monitor device (Brand name - LINQ device, Medtronic - referred to in the application as "implantable loop recorder" or "ILR")

Implantation of an implantable cardiac monitor device (brand name LINQ device, Medtronic) will be performed under local anaesthetic using an aseptic sterile technique. They will undergo frequent follow-up and monitoring for arrhythmias through remote monitoring of the device

LINQ device - implantable cardiac monitor - referred to in the application as "implantable loop recorder" or "ILR")

Marianna Fontana

Rishi K Patel

The overall aim of this study is to improve our understanding of the effects of the build-up of amyloid deposits in the heart, in particular, our understanding of the risk of abnormal heart beats, or rhythms, associated with people with cardiac (heart) amyloidosis. Symptoms such as palpitations (fast, strong or irregular heart beat) and blackouts are common in people with cardiac amyloidosis, but there is not enough information on what causes this. At present, there is also not enough information on when they occur, how often they happen, and which patients are at risk of having serious, life-threatening types of abnormal heart rhythms.

Some of these abnormal heart rhythms can be treated with medicine; others need electronic devices (e.g. pacemakers) implanted or inserted in the heart to prevent serious harm. The information on when is the best time to implant these life-saving devices remains limited. In this study, a small device known as an implantable loop recorder (ILR) will be implanted under the skin on the chest wall to continuously monitor participants' heart rhythm.

This will help us answer some of the questions about what causes the abnormal heart rhythms, when they happen, and which patients are particularly likely to have them. Furthermore, it may help us to identify earlier, rather than later, those who are at risk of developing abnormal heart rhythms. This may lead to improvements in the care of people with cardiac amyloidosis in the future. Participants may not directly benefit from taking part in this study; however, there is a chance that the ILR may reveal heart rhythm abnormalities in some participants which might not be picked up otherwise, and so may lead to a change in their treatment.

Sudden cardiac death (SCD) occurs in up to 1/3 of patients with AL amyloidosis within the first 90 days but conflicting findings have been reported on the mechanism. Electromechanical dissociation (EMD) is thought to account for some 6-7 cases, underscoring doubts about a role for implantable cardioverter-defibrillators (ICDs). However, there are studies that have described appropriate and effective ICD therapies in 27% to 32% of cases, similar to primary prevention in other disorders. The strength of evidence in all these studies is fairly weak (small, single-centre, retrospective, not linked to mechanism), but this potentially makes ICD implantation more important than in other conditions. It has also been shown in a study with small patient numbers that the pre-terminal event is often bradycardia, which may be amenable to pacemaker therapy. At present, the available information regarding arrhythmia burden in cardiac amyloidosis is limited, and further data are crucial to better guide patient selection for device therapy.

Whilst the burden of arrhythmia and sudden cardiac death appear considerable, there is limited characterisation of the incidence and predictive factors for arrhythmia requiring treatment. Cardiac involvement is the main driver of outcome in cardiac amyloidosis. Amyloidosis is a continuum from small focal amyloid deposits to extensive diffuse myocardial infiltration. The dynamic and progressive nature of amyloid deposition is likely to create an arrhythmogenic substrate that alters over time. For example, patchy amyloid deposits occurring in earlier disease might potentially provide an anatomical substrate enabling re-entry and underlie ventricular tachyarrhythmias, whilst diffuse transmural amyloid deposition may increase risk of AV block and bradyarrythmias. The investigators believe that amyloid deposition will be associated with increased risk of fatal arrhythmias, including AV block, bradyarrhythmias and ventricular arrhythmias. There are no current criteria or arrhythmia risk stratification available to guide device implantation in patients with cardiac amyloidosis. There are also limited data available on predictive disease characteristics that promote arrhythmia

Current monitoring for arrhythmia involves routine 12-lead ECG checks at annual or six-monthly clinic visits. Longer durations of monitoring (24- or 72-hour Holter monitoring or implantable loop recorders, ILR) are undertaken only when clinically indicated. Other cardiac investigations that are routinely performed in cardiac amyloidosis include echocardiography and cardiac magnetic resonance (CMR) imaging.

Current management of arrhythmia is limited to anticoagulation as per the CHADS2VASC score for atrial fibrillation, and permanent pacemaker insertion for standard indications including high degree atrioventricular blocks. There are limited data available to inform insertion of defibrillators, and this is currently assessed on a case by case basis.

Cardiac biomarkers may be helpful in raising clinical suspicion of cardiac amyloidosis patients with known plasma cell dyscrasia and should prompt further investigation with electrocardiogram (ECG) and echocardiography. The combination of cardiac biomarkers serum N-terminal prohormone of brain natriuretic peptide (NT-proBNP) and troponin is useful to stratify prognosis and guide treatment strategies in AL amyloidosis. In these patients, ECG tends to show low voltage complexes with common observations including repolarisation abnormalities, pseudo-infarction patterns, left anterior hemiblock, ischaemic or non-specific T wave abnormalities, and rhythm disturbances such as atrial fibrillation. Echocardiography shows the cardiac amyloid phenotype is a thick-walled ventricle, small left ventricular chamber volume, valve thickening, atrial enlargement and signs of elevated filling pressures with a restrictive diastolic filling.

CMR is at the forefront of diagnosis and monitoring of cardiac amyloidosis. CMR uses its intrinsic capacity to characterise cardiac tissue on the basis of fundamental MR properties (T1 and T2), and these intrinsic properties can be strengthened by administration of gadolinium-based contrast agents. CMR can visually depict, with late gadolinium enhancement (LGE), and quantify, with T1 mapping, the continuum of cardiac amyloid deposition allowing for noninvasive measurement of cardiac amyloid burden. Transmurality of LGE, elevation in native T1 and extracellular volume fraction (ECV) all correlate with amyloid burden.

In a study from the UK National Amyloidosis Centre (NAC) published in 2015, ILRs were inserted into 20 consecutive patients with severe cardiac AL amyloidosis. The most important finding was that the terminal syncopal phase prior to death revealed initial cardiac decompensation to be associated with marked bradycardia usually caused by complete heart block, subsequently followed by pulseless electrical activity. But this study was done in patients with end stage AL amyloidosis, and rhythm disturbances in the wide spectrum of amyloid infiltration has never been studied.

Currently, arrhythmia risk prediction is limited despite existing structural and functional assessment tools. ILR data would provide invaluable information on arrhythmia burden, which may be correlated with information obtained from the existing standard-of-care (SOC) structural, biochemical and functional assessments such as, but not limited to, T1 mapping and ECV from CMR, serum biomarkers, and the six-minute walk test (6MWT). These data together would provide a global picture of the arrhythmia burden and contributing risk factors; this has the potential to transform our understanding of arrhythmia in cardiac amyloidosis.

Furthermore, improvements in ILR technology have made these devices more patient-friendly. New ILRs no longer require surgical implantation but can be subcutaneously injected in the outpatient setting. They are simple to use, with automatic recording and uploading of data over each 24-hour period for up to 3 years.

An ILR is a small injectable electronic device (approximate size 45 x 7 x 4 mm, about one-third the size of a AAA battery), which is inserted under the skin within the subcutaneous tissue in the chest. It is routinely used for continuous cardiac monitoring for a range of symptoms (syncope, pre-syncope or palpitations of suspected cardiac origin, arrhythmia) in the wider National Health Service (NHS), and at the Royal Free Hospital (RFH). The required incision for device insertion is less than 1 cm, and it can safely be inserted by a trained healthcare professional (HCP) in the outpatient setting. It is safe and well-tolerated once inserted. One suture is required to close the wound.

As with any such procedure there is a small risk of bleeding and/or infection, both of which are rare. The risk of infection may be minimised by the maintenance of aseptic technique and sterile environment throughout the procedure. Patients will remain in the department under observation for 1 hour after the procedure, and the insertion site will be checked for bleeding and any other abnormalities before the patient is allowed to leave.

Patients will attend their GP surgery (or return to the RFH, whichever is their preference) within 7 to 10 days for removal of the suture and for examination of the insertion site. The device may be removed (as per SOC) when the battery runs out or 3 years after insertion, whichever happened first. The device may be removed earlier if indicated by, for example, adverse event. The ILR may also be left in situ once the patient has completed participation or when the battery runs out, according to patient preference.

ILRs are used in routine practice where indicated for continuous cardiac monitoring in patients with later-stage cardiac amyloidosis but are not currently routinely implanted in patients with early stage disease. Although this study will involve implanting ILRs earlier on in the disease process than usual, this is not anticipated to present any additional risk to patients. Therefore the risk categorisation for this trial would be Type A: Comparable to the risk of standard medical care for this particular patient group. Furthermore, there is the potential benefit of early intervention to treat arrhythmias, which could be life-changing and possibly even life-saving for some patients.

Exploration of Arrhythmia Burden in Cardiac Amyloidosis Using Implantable Loop Recorders

Primary outcome measure is the presence of any clinically significant heart rhythm abnormality as revealed from the implantable cardiac monitor (ILR) over the course of the study

Secondary outcome measure is the correlation of heart rhythm disturbances identified from the implantable cardiac monitor (ILR), with other structural and functional variables obtained from other SOC tests such as, but not limited to, T1 mapping and ECV from CMR, serum biomarkers and the six-minute walk test (6MWT) distance

Professor of Cardiology and Clinical Lead of the UCL Cardiac CMR service

After enrolment, patients will be subjected to diagnostic procedures according to standard of care to resolve diagnostic uncertainties and to clarify possible cardiac involvement. The results of the clinical work-up will be used a standard of truth, i.e. patients with initially suspected cardiac amyloidosis that where subsequently clinically diagnosed with cardiac AL Amyloidosis, cardiac ATTR Amyloidosis, other cardiac Amyloidosis or non cardiac amyloidosis.

All enrolled patients will undergo \[18F\]florbetaben PET imaging.

[18F]florbetaben

Iris Hardewig, PhD

Aleksandar Jovalekic, PhD

Andrew Stephens, MD, PhD

This is an open-label, multi-center pivotal Phase 3 study to visually and quantitatively assess PET images obtained after single application of 300 MBq \[18F\]florbetaben and PET scanning of patients with suspected cardiac amyloidosis.

This is an open-label, multi-center pivotal Phase 3 study to visually and quantitatively assess PET images obtained after single application of 300 MBq \[18F\]florbetaben and PET scanning of patients with suspected cardiac amyloidosis or with a putative diagnosis of cardiac amyloidosis but with remaining diagnostic uncertainty (e.g., unclear etiology or cardiac manifestation) or patients with diagnosis of amyloidosis but unclear cardiac involvement.

The diagnostic efficacy of the visual and quantitative assessments of \[18F\]florbetaben PET images for diagnosis of cardiac AL Amyloidosis will be determined by comparison to the standard of truth (SoT) obtained through standard of care clinical diagnosis.

All eligible patients will receive a single administration of the imaging agent \[18F\]florbetaben at a radioactive dose of 300 MBq.

Efficacy of [18F]Florbetaben PET for Diagnosis of Cardiac AL Amyloidosis

An Open-label, Multi-center, Non-randomized Pivotal Phase 3 Study to Evaluate the Efficacy and Safety of [18F]Florbetaben Positron Emission Tomography (PET) Imaging to Diagnose Cardiac AL Amyloidosis

In this exploratory endpoint the sensitivity and specificity of \[18F\]florbetaben PET images for a differential diagnosis between AL CA, ATTR CA and non CA will be assessed.

The results from the visual assessment of \[18F\]florbetaben PET images are compared to the clinical diagnosis established through histological verification of the presence or absence of AL amyloidosis with cardiac involvement determined either through endomyocardial biopsy or through extracardiac biopsy in conjunction with typical CMR or echocardiography imaging features as the standard of truth.

The sensitivity and specificity of \[18F\]florbetaben PET for the diagnosis of cardiac AL amyloidosis will be determined by using quantitative image analysis.

Correlation of quantitative \[18F\]florbetaben PET results with left ventricular ejection fraction (LV EF) and left ventricular mass (LV mass).

Correlation of quantitative \[18F\]florbetaben PET results with AL CA stage I - IV based on FLC-diff, cTnT and NT-proBNP levels.

The impact of PET imaging (AL-CA/non AL-CA) on diagnostic thinking and patient management will be assessed with physician's questionnaires before and after the diagnostic work-up, and after receipt of the PET results.

Safety will be evaluated by collection of Adverse Events.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Amyloidosis Incidence in High-Risk Cardiac Device Patients	NCT06186167	Amyloid Cardiac Amyloid... Amyloidosis Car... Systemic Amyloi... AL Amyloidosis Infiltrative Ca... ATTR Amyloidosi...	Chest Wall Fat ...	40 Years -	Midwest Heart & Vascular Specialists
Exploration of Arrhythmia Burden in Cardiac Amyloidosis Using Implantable Loop Recorders	NCT04856267	Arrythmia Cardiac Amyloid... Systemic AL Amy... Sudden Cardiac ...	LINQ device - i...	18 Years -	Royal Free Hospital NHS Foundation Trust
Amyloidosis Incidence in High-Risk Cardiac Device Patients	NCT06186167	Amyloid Cardiac Amyloid... Amyloidosis Car... Systemic Amyloi... AL Amyloidosis Infiltrative Ca... ATTR Amyloidosi...	Chest Wall Fat ...	40 Years -	Midwest Heart & Vascular Specialists
Amyloidosis Incidence in High-Risk Cardiac Device Patients	NCT06186167	Amyloid Cardiac Amyloid... Amyloidosis Car... Systemic Amyloi... AL Amyloidosis Infiltrative Ca... ATTR Amyloidosi...	Chest Wall Fat ...	40 Years -	Midwest Heart & Vascular Specialists
Efficacy of [18F]Florbetaben PET for Diagnosis of Cardiac AL Amyloidosis	NCT05184088	Cardiac Amyloid... AL Amyloidosis ATTR Amyloidosi...	[18F]florbetabe...	18 Years -	Life Molecular Imaging SA
Exploration of Arrhythmia Burden in Cardiac Amyloidosis Using Implantable Loop Recorders	NCT04856267	Arrythmia Cardiac Amyloid... Systemic AL Amy... Sudden Cardiac ...	LINQ device - i...	18 Years -	Royal Free Hospital NHS Foundation Trust

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