Ventricular tachyarrhythmias and sudden cardiac death in light‐chain amyloidosis: a clash of cardio‐toxicities?

Abstract

Sudden cardiac death (SCD) is not uncommon in immunoglobulin light-chain amyloidosis (AL) and has been usually attributed to pulseless electrical activity (PEA) or agonal bradycardia occurring in the late stages of the cardiomyopathy. In addition, the historically reported survival of <12 months in patients with cardiac AL has represented a contraindication to an implantable cardioverter defibrillator (ICD). Reports based on small series have further discouraged use of an ICD in this disease. However, recently, the evolution of treatment options has improved overall survival, opening new perspectives in terms of cardiac protection, and calling for further understanding of the arrhythmic profile and SCD prevention in patients with AL. Following the repeated observation of potentially lethal ventricular tachyarrhythmias in patients with AL, we retrospectively analysed 66 consecutive patients diagnosed with AL at a tertiary referral centre (Careggi University Hospital, Florence, Italy), between January 2016 and December 2019, to assess the prevalence and clinical setting of cardiac arrest and SCD. For the purpose of this study, aborted cardiac arrest and appropriate ICD shock were considered as SCD equivalents. The mean (SD) age of the 66 patients was 67 (10) years, 44 (67%) males. Cardiac involvement was diagnosed in 56 (84%) patients. For the main demographic, baseline features and chemotherapeutic approaches see Table S1. At a mean (SD) of 6 (3) months from diagnosis of AL amyloidosis, eight patients (12%) had SCD. Of these, four (6%) had resuscitated cardiac arrest (of whom, one subsequently died of refractory heart failure, patient 6; Fig 1, Table I) whereas four died (Fig 1, Table I). The remaining three patients were alive at census date (September 2020), at a mean (SD) 28 (7) months from cardiac arrest (Fig 1, Table I). All eight patients with SCD had known AL cardiac involvement, whereas cardiac involvement was present in 48 (82%) of patients not experiencing SCD. There were no statistical differences in the main clinical characteristics between patients with and without SCD, although the mean interventricular septum wall thickness was greater in patients with SCD (Table S1). The mean left ventricle ejection fraction (LVEF) between the two groups was comparable. The LVEF in patients experiencing SCD ranged from 45% (mild reduction) to 65% (normal) and in patients without SCD ranged from 30% (severely impaired) to 69%; therefore EF may prove falsely reassuring in discriminating patients at risk of SCD. All patients with SCD underwent cyclophosphamide/ bortezomib/dexamethasone (CyBorDex) as their first-line chemotherapy approach; in patients without SCD, CyBorDex was the most common type of first-line treatment accounting for 45% of chemotherapeutic approaches (Table S1). In four of the eight patients with SCD, the presenting rhythm was a documented hyperkinetic ventricular arrhythmia (ventricular tachycardia or ventricular fibrillation); among the remaining four patients, PEA was the presenting rhythm in one whereas in three the presenting rhythm was unknown (Table I, Fig 1). Three of the four patients with hyperkinetic ventricular arrhythmias received an ICD in secondary prevention; one patient with ventricular tachycardia did not receive an ICD because of advanced heart failure and poor life expectancy (Patient 6 Table I, Fig 1). Excluding Patient 6, all patients survived to cardiac arrest initiated antiarrhythmic therapy with b-blockers or amiodarone. One patient with an ICD had multiple appropriate shocks during follow-up (Patient 5 Fig 1). All patients with an ICD were alive at census date and classified as functional New York Heart Association (NYHA) Class II or III (Patient 5, 7, 8 Fig 1, Table I). Of note, all patients that experienced SCD did so during chemotherapy and in only one case an appropriate shock occurred during the remission period. In seven patients, SCD occurred during CyBorDex treatment (Fig 1). One patient experienced resuscitated SCD due to ventricular tachyarrhythmia during second-line treatment with lenalidomide/ dexamethasone (Patient 6, Fig 1). Furthermore, one patient with previous resuscitated SCD during CyBorDex, had an appropriate ICD shock due to ventricular tachyarrhythmia in a chemotherapy-free remission period and multiple arrhythmic events triggering ICD interventions, during daratumumab/lenalidomide/dexamethasone course for AL relapse (Patient 5 Fig 1). We think there are two main findings in the present study: 1 Patients with AL and cardiac involvement are prone to SCD, mediated by ventricular tachyarrhythmias at least as often as atrioventricular block or PEA – contradicting a long-held belief. 2 Life-threatening ventricular tachyarrhythmias cluster almost exclusively during chemotherapy cycles, suggesting correspondence