Magri D; Sant’Andrea Hospital, ‘Sapienza’ University of Rome, Italy
Ermolaev N; Castiglione V; Willixhofer R; et al

ESC heart failure. 13(4), 2026 Jul 04.

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 naive 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.