Exploration of Arrhythmia Burden in Cardiac Amyloidosis Using Implantable Loop Recorders

Sudden cardiac death (SCD) occurs in up to 1/3 of patients with cardiac amyloidosis 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, while NT-proBNP and estimated glomerular filtration rate are used to stratify prognosis in transthyretin amyloid cardiomyopathy (ATTR-CM). 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.