Exploration of Arrhythmia Burden in Cardiac Amyloidosis Using Implantable Loop Recorders
Exploration of Arrhythmia Burden in Cardiac Amyloidosis Using Implantable Loop Recorders
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.
Inclusion Criteria:

 -  Age over 18 years

 -  Diagnosed with cardiac AL amyloidosis using standard diagnostic techniques and
 criteria at the NAC

 -  Willing and able to provide written informed consent

 Exclusion Criteria:

 -  Patient who already have a cardiac device inserted, such as a permanent pacemaker
 (PPM), implantable cardioverter-defibrillator (ICD) or implantable cardiac monitor
 (ILR)

 -  Other pre-existing cardiac or other pathology which, in the investigators opinion,
 would adverse affect primary outcome data collection

 -  Contraindication to CMR imaging