Increased Pacemaker Lower Rate in ATTR Cardiac Amyloidosis

Transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly recognized cause of restrictive cardiomyopathy, characterized by reduced ventricular compliance, low stroke volume, and marked dependence on heart rate for maintenance of cardiac output. Conduction disease is common in ATTR-CM, and a substantial proportion of patients require permanent pacemaker implantation.

Although disease-modifying therapy can slow disease progression, evidence guiding optimization of pacemaker therapy in ATTR-CM is lacking. In heart failure with preserved ejection fraction, a condition also characterized by reduced ventricular compliance, increased pacemaker lower rate settings have been shown to improve functional capacity and quality of life. However, patients with cardiac amyloidosis were excluded from these studies. Consequently, current practice in ATTR-CM relies largely on extrapolation and expert opinion.

In this randomized multicenter 2×2 crossover trial, we aim to determine whether a higher pacemaker lower rate (80 bpm) improves health-related quality of life (QoL) and functional capacity in patients with ATTR-CM compared with the standard setting of 60 bpm.

Inclusion criteria

• ATTR-CM defined as one of the following:
• a.Positive cardiac biopsy for ATTR amyloidosis
• b.Positive extra-cardiac biopsy for ATTR amyloidosis AND cardiac involvement demonstrated by CMR or echocardiography
• c.Grade 2-3 uptake on DPD-scintigraphy AND negative serum free light chain and negative urine and serum immunofixation AND cardiac involvement demonstrated by CMR or echocardiography
• Ongoing treatment with a transthyretin stabilizer or silencer OR considered not to be a candidate for these therapies with no planned initiation during the study period.
• NYHA functional class II-III
• Pre-existing pacemaker and either:
• a.Atrial pacing with minimal RV pacing (<2%), or
• b.His bundle or left bundle branch area pacing, or
• c.Biventricular pacing, or
• d.Ongoing RV pacing with a high degree of RV pace (>80%)
• NT-proBNP >600 ng/L
• Age ≥18 years
• Ability and willingness to provide written informed consent
• Pacing >80% with a programmed lower rate of 60 (AAI/CSP/CRT/RV-pace)

Exclusion criteria

• Inability to perform the 6-minute walk test.
• Planned coronary revascularization, ablation of atrial flutter/fibrillation, or any severe (obstructive or regurgitant) valvular heart disease expected to require intervention during the trial in the investigator's opinion.
• MI, unstable angina, coronary revascularization (percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG)), ablation of atrial flutter/fibrillation, cardioversion, valve repair/replacement, hospitalization for decompensated heart failure or cardiac resynchronisation therapy within 12 weeks prior to enrollment.
• Planned upgrade to CRT or conduction system pacing in patients with RV pacing.
• More than moderate valvular stenosis or regurgitation
• Inability of the patient, in the opinion of the investigator, to understand and/or comply with procedures and/or follow-up OR any conditions that, in the opinion of the investigator, may render the patient unable to complete the study
• Presence of any other disease than heart failure with a life expectancy of < 1year in the investigators opinion
• Enrollment in other interventional device or drug trials during the study period, with the exception of open label extension studies
• Listed for cardiac transplantation
• Initiation of SGLT2-inhibitor or mineralocorticoid receptor antagonist within 4 weeks prior to enrollment
• Initiation or change in loop diuretic therapy within 4 weeks prior to enrollment