Prognostic impact of chronotropic incompetence in transthyretin cardiac amyloidosis: a multicentre study

Introduction: Chronotropic incompetence (CI) is a frequent but underappreciated feature of cardiac amyloidosis and may contribute to exercise intolerance. However, its prognostic significance remains incompletely defined. We investigated the prevalence, functional correlates, and prognostic value of chronotropic incompetence in patients with transthyretin amyloid cardiomyopathy. Methods: In this multicentre retrospective study, 212 stable outpatients with transthyretin amyloid cardiomyopathy, in sinus rhythm and naïve to disease-specific therapy, underwent maximal cardiopulmonary exercise testing. Chronotropic response was assessed as peak heart rate expressed as a percentage of the age-predicted value (pHR%). Chronotropic incompetence prevalence was evaluated using clinically relevant thresholds. Prognostic performance for 1-year cardiovascular mortality was assessed using Cox regression, receiver operating characteristic analysis, and Kaplan–Meier estimates. Results: Chronotropic incompetence defined by a pHR% ≤75% was present in 35% of patients and was associated with markedly impaired functional capacity, including lower peak oxygen uptake and reduced ventilatory efficiency. During 1-year follow-up, 10 cardiovascular deaths occurred. Among exercise-derived variables, pHR% demonstrated strong prognostic value, with each 1% increase associated with a 5.5% relative reduction in cardiovascular mortality risk (hazard ratio 0.945; P = .011). A pHR% threshold of 75% provided optimal discrimination (area under the curve 0.71) and identified a subgroup with significantly lower survival (log-rank P < .05). Conclusion: A blunted chronotropic response is common in transthyretin amyloid cardiomyopathy and conveys adverse short-term prognosis. A pHR% ≤75% represents a clinically meaningful and easily obtainable threshold for functional and prognostic stratification, offering a pragmatic alternative when comprehensive cardiopulmonary exercise testing assessment is not available.