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Participants who will receive the Implantable Loop Recorder (Reveal-LINQ) inserted just after baseline. This is single intervention and lasts for 3 years after which the patient has the option to have it removed.

Participants who will not get the Implantable Loop Recorder (Reveal-LINQ).

Insertion of monitoring device called Reveal-LINQ (an implantable loop recorder)

Reveal LINQ

This study is a prevelance trial looking at how sleep apnoea affects the heart especially heart rhythms.

Previous research shows that patients suffering from sleep apnoea are much more likely to get heart disease and abnormal heart rhythms (arrhythmias). These defects are sometimes missed by the traditional methods of monitoring i.e. 24-hour Holter monitor and ECGs. This means potentially dangerous arrhythmias may not be detected. Additionally, standard therapy for sleep apnoea does not significantly reduce the risk of heart disease.

This study will recruit 200 participants over a period of 18 months. The research team will observe the heart rhythms of sleep apnoea patients by inserting an implantable loop recorder (ILR) in up to 100 participants. The other 100 patients will simply have standard care. This device will monitor the heart continuously for 3 years allowing us to detect abnormal heart rhythms and treat as necessary.

Demonstrating the incidence of arrhythmia can lead onto a larger study which may change future sleep apnoea management improving their cardiovascular outcomes. Other markers of heart disease such as; blood tests, Magnetocardiography and Echocardiography will be performed on participants to shed more light on the mechanisms which link sleep apnoea and heart disease/arrhythmia.

Sleep apnoea affects up to 1.5 million adults in the United Kingdom (UK). This puts this population at risk of reduced oxygen levels during sleep, poor sleep and increased breathing effort . All of the above put stress on the body and are proven to increase the risk of high blood pressure, heart failure and vascular problems. This can lead to strokes, heart disease and death.

Sleep apnoea patients are at much higher risk of abnormal heart rhythms. Even with continuous positive airways pressure (CPAP) treatment (which is the mainstay in sleep apnoea and does help to reduce arrhythmias) patients are still at higher risk of heart disease and stroke.

An implantable loop recorder (Reveal-LINQ) inserted into sleep apnoea patients will be able to continuously monitor a patient's heart rhythm. This will determine the incidence of arrhythmia in sleep apnoea patients. Any significant abnormalities in either arm of the study will be treated as per National Health Service guidelines and best care. The cost associated with this method of intervention will also be considered.

If there is a high prevalence of arrhythmia a future larger trial, involving much larger numbers and multiple centres, could be conducted to demonstrate reduced risk of stroke or heart attack using this method of arrhythmia detection and management.

Cardiovascular biomarkers, cardiac function, autonomic function and magnetocardiography in these patients could shed light on the mechanisms which cause increased cardiovascular morbidity and mortality.

2 groups with the intervention the difference.

Obstructive Sleep Apnoea and Cardiac Arrhythmias

Obstructive Sleep Apnoea and Cardiac Arrhythmias and the Impact of an Implantable Loop Recorder

Incidence of arrhythmia in sleep apnoea patients as recorded by ILR vs a no ILR group

Assess the changes to the heart in sleep apnoea patients before and after CPAP in terms of heart rate variability as measured on 24 hour holter monitors. The raw data is taken from the monitor and then analysed manually. The first data set will be from baseline studies which will be compared to studies done at the 1 year follow-up.

Explore the onset and frequency of atrial fibrillation in sleep apnoea patients in order to determine what method of detection is efficient and cost effective.

Explore the impact of inserting an ILR in patients with sleep apnoea on cardiovascular morbidity (stroke and myocardial infarction) compared to those without ILR

Explore the impact of inserting an ILR in patients with sleep apnoea on cardiovascular mortality (stroke and/or myocardial infarction resulting in death) compared to those without ILR

Explore the changes to the heart in sleep apnoea patients before and after CPAP in terms of vascular biomarkers - high sensitivity C-Reactive Protein, high sensitivity Troponin-T, N-terminal pro B-type Natriuretic Peptide, Tumour Necrosis Factor-alpha, Matrix Metalloproteinase-9, Interleukin-6, Fibroblast Growth Factor-23. The first data set will be from baseline studies which will be compared to studies done at the 1 year follow-up.

Explore the changes to the heart in sleep apnoea patients before and after CPAP in terms of echocardiogram measures.

Quality of life measures before and after CPAP as measured by the EQ-5D 5 level questionnaire. This measures various quality of life points from a scale of 1-5. 1 represents poor quality of life and 5 represents good quality of life for each factor. This data will be analysed as per the EuroQol algorithm. The first data set will be from baseline studies which will be compared to studies done at the 1 year follow-up.

University Hospitals Coventry and Warwickshire NHS Trust

Nutritional and Metabolic Diseases

Neoplasms

Blood and Lymph Conditions

Rare Diseases

Amyloidosis

Death

Immunoglobulin Light-chain Amyloidosis

Death, Sudden, Cardiac

Death, Sudden

Proteostasis Deficiencies

Metabolic Diseases

Heart Arrest

Neoplasms, Plasma Cell

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Immunoproliferative Disorders

Paraproteinemias

AL Amyloidosis

Central Nervous System Depressants

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

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Obstructive Sleep Apnoea and Cardiac Arrhythmias	NCT03866148	Obstructive Sle... Cardiovascular ... Arrhythmia Atrial Fibrilla...	Reveal LINQ	18 Years - 75 Years	University Hospitals Coventry and Warwickshire NHS Trust
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
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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